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Characterizing the dynamics of CD4+ T cell priming within a lymph node.

ABSTRACT: Generating adaptive immunity postinfection or immunization requires physical interaction within a lymph node T zone between Ag-bearing dendritic cells (DCs) and rare cognate T cells. Many fundamental questions remain regarding the dynamics of DC-CD4+ T cell interactions leading to priming. For example, it is not known how the production of primed CD4+ T cells relates to the numbers of cognate T cells, Ag-bearing DCs, or peptide-MHCII level on the DC. To address these questions, we developed an agent-based model of a lymph node to examine the relationships among cognate T cell frequency, DC density, parameters characterizing DC-T cell interactions, and the output of primed T cells. We found that the output of primed CD4+ T cells is linearly related to cognate frequency, but nonlinearly related to the number of Ag-bearing DCs present during infection. This addresses the applicability of two photon microscopy studies to understanding actual infection dynamics, because these types of experiments increase the cognate frequency by orders of magnitude compared with physiologic levels. We found a trade-off between the quantity of peptide-major histocompatibility class II on the surface of individual DCs and number of Ag-bearing DCs present in the lymph node in contributing to the production of primed CD4+ T cells. Interestingly, peptide-major histocompatibility class II t(1/2) plays a minor, although still significant, role in determining CD4+ T cell priming, unlike the primary role that has been suggested for CD8+ T cell priming. Finally, we identify several pathogen-targeted mechanisms that, if altered in their efficiency, can significantly effect the generation of primed CD4+ T cells.

SUBMITTER: Linderman JJ

PROVIDER: S-EPMC3153313 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Characterizing the dynamics of CD4+ T cell priming within a lymph node.

Linderman Jennifer J JJ Riggs Thomas T Pande Manjusha M Miller Mark M Marino Simeone S Kirschner Denise E DE

Journal of immunology (Baltimore, Md. : 1950) 20100212 6

Generating adaptive immunity postinfection or immunization requires physical interaction within a lymph node T zone between Ag-bearing dendritic cells (DCs) and rare cognate T cells. Many fundamental questions remain regarding the dynamics of DC-CD4+ T cell interactions leading to priming. For example, it is not known how the production of primed CD4+ T cells relates to the numbers of cognate T cells, Ag-bearing DCs, or peptide-MHCII level on the DC. To address these questions, we developed an a ...[more]

PMID: 20154206

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Project description:The adaptive immune response is initiated in lymph nodes by contact between antigen-bearing dendritic cells (DCs) and antigen-specific T cells. A selected number of naïve T cells that recognize a specific antigen may proliferate into expanded clones, differentiate, and acquire an effector phenotype. Despite growing experimental knowledge, certain mechanistic aspects of T cell behavior in lymph nodes remain poorly understood. Computational modeling approaches may help in addressing such gaps. Here we introduce an agent-based model describing T cell movements and their interactions with DCs, leading to activation and expansion of cognate T cell clones, in a two-dimensional representation of the lymph node paracortex. The primary objective was to test the putative role of T cell chemotaxis toward DCs, and quantitatively assess the impact of chemotaxis with respect to T cell priming efficacy. Firstly, we evaluated whether chemotaxis of naïve T cells toward a nearest DC may accelerate the scanning process, by quantifying, through simulations, the number of unique T cell-DC contact events. We demonstrate that, in the presence of naïve T cell-to-DC chemoattraction, a higher total number of contacts occurs, as compared to a T cell random walk scenario. However, the forming swarm of naïve T cells, as these cells get attracted to the neighborhood of a DC, may then physically restrict access of additional T cells to the DC, leading to an actual decrease in the cumulative number of unique contacts between naïve T cells and DCs. Secondly, we investigated the potential role of chemotaxis in maintaining cognate T cell clone expansion. The time course of cognate T cells number in the system was used as a quantitative characteristic of the expansion. Model-based simulations indicate that inclusion of chemotaxis, which is selective for already activated (but not naïve) antigen-specific T cells, may strongly accelerate the time of immune response occurrence, which subsequently increases the overall amplitude of the T cell clone expansion process.

Dataset Information

Characterizing the dynamics of CD4+ T cell priming within a lymph node.

Publications

Characterizing the dynamics of CD4+ T cell priming within a lymph node.

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