Environmental Control of the Immunological Synapse

描述(申请人提供)：适应性免疫反应是由T细胞-抗原递呈细胞在2-3天内在淋巴结和脾内相互作用而启动的。这种相互作用的调节可能在正常免疫反应和自身免疫等病理过程中T细胞的增殖和分化中发挥关键作用。T细胞和APC最初的相互作用是幼稚T细胞在T细胞区快速迁移的结果，这可以被描述为有偏见的随机行走。我们假设这种有偏见的随机行走是基于趋化因子提供对T细胞区的偏向，以及趋化运动因子刺激淋巴结内随机定向的迁移成分。血栓素A2和鞘氨醇-1-磷酸等化学动力学因子参与调节T细胞对抗原的反应。激动剂MHC-肽复合体可在数小时内阻止T细胞在活体小鼠的淋巴结内迁移，并可导致稳定的免疫突触的形成。我们进一步假设，趋化和趋化GO信号和抗原停止信号之间的竞争对于在初始反应期间设定T细胞激活的阈值将是重要的。例如，我们已经发现，这种停止信号可以被趋化因子梯度与主要趋化因子受体CCR7相互作用逆转，但不能被趋化因子梯度与从属趋化因子受体CXCR4相互作用逆转。我们将通过三个具体目标来检验这两个相互关联的假设。在目标1中，我们将研究有偏随机游走在淋巴结和脾的T细胞区的机制。在目标2中，我们将确定不同形式的激动剂MHC-肽复合体对T细胞在淋巴结中迁移的影响。在目标3中，我们将研究主导和从属趋化因子行为的基础，并将寻求修改体内的层次结构，以测试这些层次结构对初级免疫反应的影响。

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.