Environmental Control of the Immunological Synapse

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DESCRIPTION (provided by applicant): The adaptive immune response is initiated by T cell-antigen presenting cell interactions in lymph nodes and the spleen during a 2-3 day period. The regulation of this interaction is likely to play a key role in the T cell proliferation and differentiation in normal immune responses and pathological processes such as autoimmunity. The initial interaction of T cells and APC is a result of rapid migration of naive T cells in the T cell zones that could be described as a biased random walk. We hypothesize that this biased random walk is based on chemokines to provide the bias toward the T cell zone and chemokinetic factors that stimulate the randomly directed component of migration within the lymph node. Chemokinetic factors like thromboxane A2 and sphingonsine-1-phosphate have been implicated in regulation of T cell responses to antigen. Agonist MHC-peptide complexes stop migration of T cells for a period of hours in lymph nodes of live mice and can lead to formation of a stable immunological synapse. We further hypothesize that the competition between the chemokinetic and chemotactic go signals and the antigen stop signal will be important for setting thresholds for T cell activation during the primary response. For example, we have discovered that this stop signal can be reversed by gradients of chemokines interacting with dominant chemokine receptor CCR7, but not by chemokine gradients interacting with subordinate chemokine receptor CXCR4. We will test these two interrelated hypotheses through three specific aims. In Aim 1 we will investigate the mechanism of the biased random walk in the T cell zones in the lymph node and spleen. In Aim 2 we will determine the effect of different forms of agonist MHC-peptide complexes on T cell migration in the lymph node. In Aim 3 we will investigate the basis of dominant and subordinate chemokine behavior and will seek to modify the hierarchy in vivo to test the impact of these hierarchies on the primary immune response.