T-cell motility in the early stages of the immune response modeled as a random walk amongst targets

Preston, Simon; Waters, Sarah L.; Jensen, Oliver E.; Heaton, Paul R.; Pritchard, D. I.

doi:10.1103/physreve.74.011910

Cited by 25 publications

(22 citation statements)

References 22 publications

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“…This observation, combined with the fact that there is a larger amount of pMHC ligands on cognate DCs at shorter times, led us to suggest that T cells may be able to integrate signals from multiple serial encounters with DCs. This aspect of our study differs from previous studies, such as a recent study by Preston et al (35), in which the detection of antigen and activation of T cells are viewed as a transport-limited process, i.e., the T cells commit to activation upon their first encounter with cognate DCs. Signal integration could result from various aspects of the T-cell signaling network that may confer memory.…”

Section: Vol 28 2008 How Antigen Dose and Type Determine T-cell Deccontrasting

confidence: 54%

How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

Zheng¹,

Jin²,

Henrickson

et al. 2008

Molecular and Cellular Biology

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T lymphocytes (T cells) express T-cell receptor (TCR) molecules on their surface that can recognize peptides (p) derived from antigenic proteins bound to products of the major histocompatibility complex (MHC) genes. The pMHC molecules are expressed on the surface of antigen-presenting cells, such as dendritic cells (DCs). T cells first encounter antigen on DCs in lymph nodes (LN). Intravital microscopy experiments show that upon entering the LN containing antigen, CD8؉ T cells first move rapidly. After a few hours, they stop and make extended contacts with DCs. The factors that determine when and how this transition occurs are not well understood. We report results from computer simulations that suggest that the duration of phase one is related to the low probability of productive interactions between T cells and DCs. This is demonstrated by our finding that the antigen dose and type determine when such a transition occurs. These results are in agreement with experimental observations. TCR-pMHC binding characteristics and the antigen dose determine the time required for a productive T-cell-DC encounter (resulting in sustained contact). We find that the ratio of this time scale and the half-life of the pMHC complex itself provide a consolidated measure of antigen quantity and type. Results obtained upon varying different measures of antigen quantity and type fall on one curve when graphed against this ratio of time scales. Thus, we provide a mechanism for how the effects of varying one set of parameters are influenced by other prevailing conditions. This understanding should help guide future experimentation.Recent multiphoton and confocal microscopy experiments have produced vivid images of the migration of T cells in lymphoid tissues during antigen recognition (2, 6-8, 11, 23, 30, 32-34, 37, 38, 40, 43, 47). For both CD4 and CD8 T cells, the motility characteristics change with time. Initially, T cells move quite rapidly upon entering the lymph node (LN). In the presence of cognate antigen, after a few hours, antigen-specific T cells slow down and make stable contacts with dendritic cells (DCs) presenting cognate antigen (6,23,30,32,33,37,38,40). For CD8 T cells, these two stages of different T-cell motility have been labeled "phase one" and "phase two" behavior (30). It seems reasonable to assume that phase one corresponds to a period during which T cells "hunt" for antigen, whereas phase two is a period of time required for signaling processes that result in a full commitment to activation (30,33). An important open question is which factors determine the time required for the transition from phase one to phase two. This is important, since this decision predicates T-cell activation and the initiation of an immune response.Several hypotheses could be considered to address this question. One is that T cells may go through such motility changes by default (30). This hypothesis implies that all antigen-specific T cells in the LN would transition into phase two synchronously and that the time at which this happe...

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Section: Vol 28 2008 How Antigen Dose and Type Determine T-cell Deccontrasting

confidence: 54%

How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

Zheng¹,

Jin²,

Henrickson

et al. 2008

Molecular and Cellular Biology

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“…This latter search has been described as having features of a Brownian random walk (Miller et al, 2003; Preston et al, 2006) or a Levy walk (Harris et al, 2012). The efficiency of this random-like motility pattern observed for T cell in lymph nodes (LN) has been heavily modeled (Beauchemin et al, 2007; Beltman et al, 2009; Textor et al, 2011); however, perturbing cellular motility patterns in vivo has not previously been possible.…”

Section: Introductionmentioning

confidence: 99%

Detection of Rare Antigen-Presenting Cells through T Cell-Intrinsic Meandering Motility, Mediated by Myo1g

Gérard

Patiño-López

Beemiller

et al. 2014

Cell

113

116

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Summary To mount an immune response, T lymphocytes must successfully search for foreign material bound to the surface of antigen-presenting cells. How T cells optimize their chances of encountering and responding to these antigens is unknown. T cell motility in tissues resembles a random or Levy walk and is regulated in part by external factors including chemokines and lymph node topology, but motility parameters such as speed and propensity to turn may also be cell-intrinsic. Here we found that the unconventional Myosin 1g (Myo1g) motor generates membrane tension, enforces cell-intrinsic meandering search and enhances T-DC interactions during lymph node surveillance. Increased turning and meandering motility, as opposed to ballistic motility, is enhanced by Myo1g. Myo1g acts as a “turning motor” and generates a form of cellular “flânerie”. Modeling and antigen challenges show that these intrinsically-programmed elements of motility search are critical for the detection of rare cognate antigen presenting cells.

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“…It is thus typically assumed that interactions between T and DC cells are transport-limited (e.g., Preston et al (2006)) or at least partially transport-controlled (e.g., Linderman et al (2010) and Riggs et al (2008)). If the process is transport-limited, activation of cognate T cells by DCs is governed by how long it takes two cells to find each other.…”

Section: Types Of Modelsmentioning

confidence: 99%

Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection

Mirsky¹,

Miller²,

Linderman³

et al. 2011

Journal of Theoretical Biology

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Adaptive immunity is initiated in secondary lymphoid tissues when naive T cells recognize foreign antigen presented as MHC-bound peptide on the surface of dendritic cells. Only a small fraction of T cells in the naive repertoire will express T cell receptors specific for a given epitope, but antigen recognition triggers T cell activation and proliferation, thus greatly expanding antigen-specific clones. Expanded T cells can serve a helper function for B cell responses or traffic to sites of infection to secrete cytokines or kill infected cells. Over the past decade, two- photon microscopy of lymphoid tissues has shed important light on T cell development, antigen recognition, cell trafficking and effector functions. These data have enabled the development of sophisticated quantitative and computational models that, in turn, have been used to test hypotheses in silico that would otherwise be impossible or difficult to explore experimentally. Here, we review these models and their principal findings and highlight remaining questions where modeling approaches are poised to advance our understanding of complex immunological systems.

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T-cell motility in the early stages of the immune response modeled as a random walk amongst targets

Cited by 25 publications

References 22 publications

How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

Detection of Rare Antigen-Presenting Cells through T Cell-Intrinsic Meandering Motility, Mediated by Myo1g

Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection

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