Santa Fe Institute Events Wiki - User contributions [en]

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Questions

2015-07-29T22:56:39Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}

<br>

Judy:
Do DCs “attract” T cells? How can we answer this experimentally or through modeling? What approaches can be used to understand cell-cell interaction/communication?
What environmental factors contribute to determining the type of search/motion taken by T cells? How do we quantitate and model these environmental influences?
What do we know about 2D vs 3D motion in other systems? Are there differences and are there models to assess these differences?

Luca:
First question for discussion:

Should a T-cell be thought of an isolated individual or are there collective or population phenomena critical to perform their tasks?

Although it is natural to start simple and hypothesize that a process occur in isolation, is there evidence that T-cells behave in the same way if in very small numbers. Modelling approaches may change dramatically if movement processes need to account for interactions with other members of a population.

Second question for discussion:

How does a single T-cell move and interact with its environment?

Before venturing to model the movement a T-cell, it is important to understand how it moves over a substrate and what are the minimal features necessary to represent its motion. Is it a fundamental mistake considering a T-cell a point particle? What is the spatial extent of a T-cell relative to the distance it travels, or relative to the spatial heterogeneity it encounters? How does it move, what cues does it react to?

Rob:

What is the role of chemotaxis of CTL within infected tissues?

Nitant:

What quantitative observations are available? What type of measurements have been done?

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Questions

2015-07-29T22:55:43Z

Mfricke: Created page with "Judy: Do DCs “attract” T cells? How can we answer this experimentally or through modeling? What approaches can be used to understand cell-cell interaction/communication? W..."

Judy:
Do DCs “attract” T cells? How can we answer this experimentally or through modeling? What approaches can be used to understand cell-cell interaction/communication?
What environmental factors contribute to determining the type of search/motion taken by T cells? How do we quantitate and model these environmental influences?
What do we know about 2D vs 3D motion in other systems? Are there differences and are there models to assess these differences?

Luca:
First question for discussion:

Should a T-cell be thought of an isolated individual or are there collective or population phenomena critical to perform their tasks?

Although it is natural to start simple and hypothesize that a process occur in isolation, is there evidence that T-cells behave in the same way if in very small numbers. Modelling approaches may change dramatically if movement processes need to account for interactions with other members of a population.

Second question for discussion:

How does a single T-cell move and interact with its environment?

Before venturing to model the movement a T-cell, it is important to understand how it moves over a substrate and what are the minimal features necessary to represent its motion. Is it a fundamental mistake considering a T-cell a point particle? What is the spatial extent of a T-cell relative to the distance it travels, or relative to the spatial heterogeneity it encounters? How does it move, what cues does it react to?

Rob:

What is the role of chemotaxis of CTL within infected tissues?

Nitant:

What quantitative observations are available? What type of measurements have been done?

Template:Motility in the Immune System: From Microscopic Movement to Macroscopic Function

2015-07-29T22:54:48Z

Mfricke:

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*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function|Home]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Agenda|Agenda]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Participants|Participants]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Abstracts|Abstracts]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Questions|Questions]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Bios|Related Papers]]
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Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T05:14:41Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}

<br>
<div id="GiuggioliAbstract"></div>'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Bristol University

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

<div id="MillerAbstract"></div>'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.<br>
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

----

<div id="CannonAbstract"></div>'''T cell motility'''

Judy Cannon

The University of New Mexico Health Sciences Center

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

----

<div id="deBoerAbstract"></div>'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

----

<div id="TextorAbstract"></div>'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

Utrecht University

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

----

<div id="PerelsonAbstract"></div>'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T05:14:16Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}

<div id="GiuggioliAbstract"></div>'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Bristol University

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

<div id="MillerAbstract"></div>'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.<br>
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

----

<div id="CannonAbstract"></div>'''T cell motility'''

Judy Cannon

The University of New Mexico Health Sciences Center

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

----

<div id="deBoerAbstract"></div>'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

----

<div id="TextorAbstract"></div>'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

Utrecht University

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

----

<div id="PerelsonAbstract"></div>'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T05:14:04Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}
<div id="GiuggioliAbstract"></div>'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Bristol University

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

<div id="MillerAbstract"></div>'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.<br>
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

----

<div id="CannonAbstract"></div>'''T cell motility'''

Judy Cannon

The University of New Mexico Health Sciences Center

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

----

<div id="deBoerAbstract"></div>'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

----

<div id="TextorAbstract"></div>'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

Utrecht University

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

----

<div id="PerelsonAbstract"></div>'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Agenda

2015-07-29T05:04:10Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}

Motility in the Immune System:
Microscopic Movement to Macroscopic Function
Working Group

July 29 – 30, 2015, 2015
Santa Fe Institute
1399 Hyde Park Road
Santa Fe, New Mexico

Co-organizers: Melanie Moses, Judy Cannon and Nitant Kenkre

Agenda

Wednesday, July 29, 2015

8:15 Shuttle departs from Hotel Santa Fe

8:30 – 9:00 Continental Breakfast at SFI

9:00 – 9:30 Welcome and introduction
:::Melanie Moses (University of New Mexico) and Judy Cannon (University of New Mexico)

9:30 – 10:00 Immunology 1: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#CannonAbstract|T cell motility]]<br>
:::Judy Cannon (University of New Mexico)

10:00 – 10:30 Immunology 2: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#MillerAbstract|T cell motility and the fibroblastic reticular network: monorails or monkey bars?]]<br>
:::Mark Miller (Washington University School of Medicine)

10:30 – 10:45 Coffee Break

10:45 – 11:15 Physics approaches 1<br>
:::Nitant Kenkre (University of New Mexico)

11:15 – 11:45 Physics approaches 2<br>
:::Marcos de Luz (Universidade Federal do Paraná)

11:45 – 12:15 Physics approaches 3: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#GiuggioliAbstract|From individual memory to environmental memory in interaction processes: animals as territorial random walkers]]<br>
:::Luca Giuggioli (University of Bristol)

12:15 – 1:30 Lunch

1:30 – 2:00 Modeling 1<br>
::: Melanie Moses (University of New Mexico)

2:00 – 2:30 Modeling 2: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#deBoerAbstract|Chemotaxis of Cytotoxic T cells in the Skin]]<br>
:::Rob de Boer (Utrecht University)

2:30 – 3:00 Coffee Break

3:00 – 3:30 Modeling 3: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#TextorAbstract|T Cell Migration: Biology, Analysis, and Clinical Relevance]]<br>
:::Johannes Textor (University of Utrecht)

3:30 – 4:00 Modeling 5: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#PerelsonAbstract|T cell Motility and the Cure of HIV]]<br>
:::Alan Perelson (Los Alamos National Laboratory)

4:00 – 5:15 Discussion

5:30 La Choza, 808 Alarid St., 505 982-0909

Thursday, July 30, 2015
8:15 Shuttle departs from Hotel Santa Fe

8:30 – 9:00 Continental Breakfast at SFI

9:00 – 9:30 Lightning talks-trainees (5min each)

9:30 – 10:40 Discussion-question 1

10:40 – 10:50 Coffee Break

10:50 – 12:00 Discussion-question 2

12:00 – 1:00 Lunch

1:00 – 2:10 Discussion-question 3

2:10 – 3:20 Discussion-question 4

3:20 – 3:30 Coffee Break

3:30 – 5:00 Paper and wrap up

5:00 End of meeting and departure

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Agenda

2015-07-29T05:03:21Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}

Motility in the Immune System:
Microscopic Movement to Macroscopic Function
Working Group

July 29 – 30, 2015, 2015
Santa Fe Institute
1399 Hyde Park Road
Santa Fe, New Mexico

Co-organizers: Melanie Moses, Judy Cannon and Nitant Kenkre

Agenda

Wednesday, July 29, 2015

8:15 Shuttle departs from Hotel Santa Fe

8:30 – 9:00 Continental Breakfast at SFI

9:00 – 9:30 Welcome and introduction
:::Melanie Moses (University of New Mexico) and Judy Cannon (University of New Mexico)

9:30 – 10:00 Immunology 1: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#CannonAbstract|T cell motility]]<br>
:::Judy Cannon (University of New Mexico)

10:00 – 10:30 Immunology 2: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#MillerAbstract|T cell motility and the fibroblastic reticular network: monorails or monkey bars?]]<br>
:::Mark Miller (Washington University School of Medicine)

10:30 – 10:45 Coffee Break

10:45 – 11:15 Physics approaches 1<br>
:::Nitant Kenkre (University of New Mexico)

11:15 – 11:45 Physics approaches 2<br>
:::Marcos de Luz (Universidade Federal do Paraná)

11:45 – 12:15 Physics approaches 3: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#GiuggioliAbstract|From individual memory to environmental memory in interaction processes: animals as territorial random walkers]]<br>
:::Luca Giuggioli (University of Bristol)

12:15 – 1:30 Lunch

1:30 – 2:00 Modeling 1<br>
::: Melanie Moses (University of New Mexico)

2:00 – 2:30 Modeling 2:[[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#deBoerAbstract|Chemotaxis of Cytotoxic T cells in the Skin]]<br>
:::Rob de Boer (Utrecht University)

2:30 – 3:00 Coffee Break

3:00 – 3:30 Modeling 3: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#TextorAbstract|T Cell Migration: Biology, Analysis, and Clinical Relevance]]<br>
:::Johannes Textor (University of Utrecht)

3:30 – 4:00 Modeling 5: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#PerelsonAbstract|T cell Motility and the Cure of HIV]]<br>
:::Alan Perelson (Los Alamos National Laboratory)

4:00 – 5:15 Discussion

5:30 La Choza, 808 Alarid St., 505 982-0909

Thursday, July 30, 2015
8:15 Shuttle departs from Hotel Santa Fe

8:30 – 9:00 Continental Breakfast at SFI

9:00 – 9:30 Lightning talks-trainees (5min each)

9:30 – 10:40 Discussion-question 1

10:40 – 10:50 Coffee Break

10:50 – 12:00 Discussion-question 2

12:00 – 1:00 Lunch

1:00 – 2:10 Discussion-question 3

2:10 – 3:20 Discussion-question 4

3:20 – 3:30 Coffee Break

3:30 – 5:00 Paper and wrap up

5:00 End of meeting and departure

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Agenda

2015-07-29T05:02:44Z

Mfricke:

{{Motility in the Immune System: From Microscopic Movement to Macroscopic Function}}

Motility in the Immune System:
Microscopic Movement to Macroscopic Function
Working Group

July 29 – 30, 2015, 2015
Santa Fe Institute
1399 Hyde Park Road
Santa Fe, New Mexico

Co-organizers: Melanie Moses, Judy Cannon and Nitant Kenkre

Agenda

Wednesday, July 29, 2015

8:15 Shuttle departs from Hotel Santa Fe

8:30 – 9:00 Continental Breakfast at SFI

9:00 – 9:30 Welcome and introduction
:::Melanie Moses (University of New Mexico) and Judy Cannon (University of New Mexico)

9:30 – 10:00 Immunology 1: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#CannonAbstract|T cell motility]]<br>
:::Judy Cannon (University of New Mexico)

10:00 – 10:30 Immunology 2: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#MillerAbstract|T cell motility and the fibroblastic reticular network: monorails or monkey bars?]]<br>
:::Mark Miller (Washington University School of Medicine)

10:30 – 10:45 Coffee Break

10:45 – 11:15 Physics approaches 1<br>
:::Nitant Kenkre (University of New Mexico)

11:15 – 11:45 Physics approaches 2<br>
:::Marcos de Luz (Universidade Federal do Paraná)

11:45 – 12:15 Physics approaches 3: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#GiuggioliAbstract|From individual memory to environmental memory in interaction processes: animals as territorial random walkers]]<br>
:::Luca Giuggioli (University of Bristol)

12:15 – 1:30 Lunch

1:30 – 2:00 Modeling 1<br>
::: Melanie Moses (University of New Mexico)

2:00 – 2:30 Modeling 2:[[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#deBoerAbstract|Chemotaxis of Cytotoxic T cells in the Skin]]<br>
:::Rob de Boer (Utrecht University)

2:30 – 3:00 Coffee Break

3:00 – 3:30 Modeling 3: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#TextorAbstract|T Cell Migration: Biology, Analysis, and Clinical Relevance]]<br>
:::Johannes Textor (University of Utrecht)

3:30 – 4:00 Modeling 5: [[Motility_in_the_Immune_System:_From_Microscopic_Movement_to_Macroscopic_Function_-_Abstracts#PerelsonrAbstract|T cell Motility and the Cure of HIV]]<br>
:::Alan Perelson (Los Alamos National Laboratory)

4:00 – 5:15 Discussion

5:30 La Choza, 808 Alarid St., 505 982-0909

Thursday, July 30, 2015
8:15 Shuttle departs from Hotel Santa Fe

8:30 – 9:00 Continental Breakfast at SFI

9:00 – 9:30 Lightning talks-trainees (5min each)

9:30 – 10:40 Discussion-question 1

10:40 – 10:50 Coffee Break

10:50 – 12:00 Discussion-question 2

12:00 – 1:00 Lunch

1:00 – 2:10 Discussion-question 3

2:10 – 3:20 Discussion-question 4

3:20 – 3:30 Coffee Break

3:30 – 5:00 Paper and wrap up

5:00 End of meeting and departure

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:53:00Z

Mfricke:

<div id="GiuggioliAbstract"></div>'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Bristol University

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

<div id="MillerAbstract"></div>'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.<br>
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

----

<div id="CannonAbstract"></div>'''T cell motility'''

Judy Cannon

The University of New Mexico Health Sciences Center

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

----

<div id="deBoerAbstract"></div>'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

----

<div id="TextorAbstract"></div>'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

Utrecht University

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

----

<div id="PerelsonAbstract"></div>'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:38:47Z

Mfricke:

<div id="GiuggioliAbstract"></div>'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Bristol University

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.<br>
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

----

'''T cell motility'''

Judy Cannon

The University of New Mexico Health Sciences Center

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

----

'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

----

'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

Utrecht University

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

----

'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:24:17Z

Mfricke:

'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Bristol University

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.<br>
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

----

'''T cell motility'''

Judy Cannon

The University of New Mexico Health Sciences Center

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

----

'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

----

'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

Utrecht University

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

----

'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:21:41Z

Mfricke:

'''From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

----

'''T cell motility and the fibroblastic reticular network: monorails or monkey bars?'''

Mark J. Miller, Ph.D.

Washington University School of Medicine, Department of Medicine, Infectious Diseases.
660 S. Euclid Ave., St. Louis MO 63110

Two-photon imaging is widely used to study cellular immune responses in mouse models of infection and inflammatory disease. In particular, the technique has led to breakthroughs in understanding the cell dynamics of leukocyte trafficking, antigen presentation and T cell activation and leukocyte effector function. In a series of papers (Miller, 2002; Miller, 2003; Miller, 2004a; Miller, 2004b, Aoshi, 2008), it was proposed that T cell receptor (TCR) repertoire scanning is a stochastic process (or agent based system) that occurs through the dynamic behavior of DC dendrites and robust T cell motility that mediates numerous random TCR-pMHC interactions. This hypothesis assumes that naïve T cell migration is relatively unconstrained in 3D and provides a foundation for agent based models (ABMs) of T cell activation kinetics and immune effector responses.
Subsequently, Bajenoff et al. proposed that T cell migration is restricted to the fibroblastic reticular conduit (FRC) network. The authors propose that because the FRC is random in structure, it provides a substrate that guides T cell migration, while also generating the "random migration" pattern characteristic of naïve T cell in vivo (Bajenoff et al., 2006). This idea has been widely adopted as dogma by immunologist, yet there are several observations that contradict this hypothesis. Moreover, T cell motility analysis methods and computer simulations are often based on the assumption that T cells can move freely within the lymph node. Whether T cells are constrained to the FRC network or not is an important issue that has ramifications for understanding the cellular mechanisms that initiate the immune response.

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'''T cell motility'''

Judy Cannon

UNM HSC

Naïve T cell move within lymph nodes (LNs) in order to maximize the likelihood of detecting pathogen infection. Dendritic cells carry antigenic material from pathogens in peripheral tissues like the lung that have been infected to LNs. T cells must interact with antigen-bearing DCs in LNs to initiate the T cell response, which is required for clearance of pathogenic infection and immunological memory. We are interested in quantitatively understanding the type of motility taken by T cells in LNs and how different types of search impacts T cell interaction with DCs. While many studies have demonstrated the functional outcome of T-DC interactions, there has been little work done to quantitate and define the precise localization of DCs. As target distribution has been shown in many biological searches to be a key factor in determining efficiency of search, we are quantitatively measuring the level of clustering, as well as total area and volume that is covered by DCs within the LN. To do this, we have imaged CD11c-YFP to label DCs in intact LNs and are measuring DC distribution. We find that DCs occupy greater volume and surface area than would be expected from the estimated DC cell size. We are also in the process of analyzing whether DCs might actively attract T cells to locations of greater DC density. We anticipate that more careful quantitation of DC targets in LNs will help to generate more accurate models of T-DC interactions.

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'''Chemotaxis of Cytotoxic T cells in the Skin'''

Ioana Niculescu<sup>3</sup>, Silvia Ariotti<sup>1</sup>, Joost Beltman<sup>2</sup>, Ton Schumacher<sup>1</sup>, Johannes Textor<sup>3</sup> & Rob J. de Boer<sup>3</sup>

Netherlands Cancer Institute (Amsterdam)<sup>1</sup>, Leiden University<sup>2</sup> & Utrecht University<sup>3</sup>

We quantify the migration of cytotoxic T lymphocytes (CTLs) within Herpes Simplex Virus-1 (HSV-1) infected epidermis in vivo. Activated T cells display a subtle distance-dependent chemotaxis towards clusters of infected cells, which is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, “bootstrapping the data” indicates that this behavior is crucial for efficient localization of CTL at the foci of infection (Ariotti et al, in revision).
We develop a computational model that includes healthy epidermis, an infection focus, CTLs that realistically squeeze between epidermal cells, follow chemotactic gradients, and kill HSV-1 infected cells. We quantify the role of chemotactic entry into the epidermis, chemotaxis within the epidermis, and chemotactic sensitivity during synapses. Controlling the infection requires chemotaxis, but too strong chemotaxis can be detrimental because (1) CTL migrate too deep into the infection focus, allowing the infection to grow at its border, and (2) chemotaxis can break functional cytotoxic synapses (Niculescu et al, in preparation).

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'''T Cell Migration: Biology, Analysis, and Clinical Relevance'''

Johannes Textor

The organs of the immune system are unique in that they largely consist of constantly
moving cells. My talk will focus on the motility of T cells, whose migration patterns
has been described as random-walk-like. I will present published and modelling results
showing how this kind of migration helps to find antigen, and how networks of fibroblastic
reticular cells (FRCs) could act to speed up this process. Next I will introduce
MotilityLab, a project in which we are building a toolkit designed to help both
experimentalists and computational biologists analyze migration data. I will end by
showing some data illustrating how understanding T cell migration could help optimize
cancer immunotherapy.

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'''T cell Motility and the Cure of HIV'''

Alan S. Perelson

Theoretical Biology & Biophysics Group<br>
Los Alamos National Laboratory<br>
Los Alamos, NM 87545<br>

During chronic infection, CD8+ T cells frequently become exhausted and express PD-1 as a cell surface marker characteristic of exhaustion. Recently, Zinsenmeyer and Dustin et al (JEM 210:757 2013) showed that exhausted CD4+ and CD8+ T cells showed prolonger motility paralysis, which could be reversed by therapeutic blockade of PD-1 PD1L interactions. Further, Hosking and Whitten et al. (JI 191:4211 2013) showed that during acute LCMV infection CD8+ T cells became exhausted 18-24 hr after infection. Motivated by these findings, Jessica Conway and I developed a model of HIV infection and treatment that includes an effector cells response that can become exhausted. I will show how this model (Conway and Perelson PNAS 112:5467 2015) provides insights into the phenomenon of post-treatment control of HIV-infection in which some patients treated with suppressive antiviral therapy have been taken off of therapy and then spontaneously control HIV infection such that the amount of virus in the circulation is maintained undetectable by clinical assays for years.

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:20:39Z

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Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:15:30Z

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Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:13:34Z

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Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:08:03Z

Mfricke:

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:07:27Z

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Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:06:51Z

Mfricke:

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T04:05:25Z

Mfricke:

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T03:52:51Z

Mfricke:

Motility in the Immune System: From Microscopic Movement to Macroscopic Function - Abstracts

2015-07-29T03:52:38Z

Mfricke: Created page with "'''Title: From individual memory to environmental memory in interaction processes: animals as territorial random walkers''' Luca Giuggioli Recent efforts in analysing spatio..."

'''Title: From individual memory to environmental memory in interaction processes: animals as territorial random walkers'''

Luca Giuggioli

Recent efforts in analysing spatio-temporal trajectories of higher level organisms aim at uncovering the role of memories in animal movement processes. It is natural to think about animals exploiting some form of memory to associate locations in the environment with high or low rewards. Examples of use of an animal's internal memory are foraging tasks when individuals return to past profitable locations, or during animal confrontations whereby individuals tend to avoid areas where they have had unsuccessful contests with a neighbour. There is however another form of memory that animals can exploit, the so-called external, or environmental, memory. It refers to situations in which individuals do not themselves retain information of past events but simply react to features that they encounter in the environment. In this scenario animal interactions may occur in the absence of internal memory with individuals reacting to stimuli found on the terrain due to the passage or marks left by another individual. This type of indirect interaction processes so far observed in eusocial insects, and coined by biologists as stigmergy, has been formulated mathematically to study the formation of territories whereby animals in a population collectively tessellate the environment in regions of exclusive use by avoiding one another rather than being attracted to specific locations over the terrain, e.g. a den or burrow. I will show that a combination of mathematical and analytical tools can be used to link some of the microscopic characteristics of the animals to those of the territories they live in.

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2015-07-29T03:49:30Z

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2015-07-29T03:48:22Z

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{|border="0" style="margin: 0px 0px 0px 10px; background: #f9f9f9; border: solid #aaa 1px;"
|'''Working Group Navigation'''
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function|Home]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Agenda|Agenda]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Participants|Participants]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Participants|Abstracts]]
*[[Motility in the Immune System: From Microscopic Movement to Macroscopic Function_-_Bios|Related Papers]]
|}