Environmental Control of the Immunological Synapse

描述（由申请人提供）：适应性免疫反应由淋巴结和脾脏的T细胞-抗原呈递细胞相互作用启动，持续2-3天。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对T细胞的增殖和分化起关键作用。T细胞和APC的初始相互作用是初始T细胞在T细胞区快速迁移的结果，这可以被描述为有偏随机游走。我们假设这种偏倚随机游走是基于趋化因子，以提供对T细胞区和趋化动力学因素的偏向，刺激淋巴结内的随机定向迁移成分。趋化动力学因子如血栓素A2和鞘氨醇-1-磷酸已参与调节T细胞对抗原的反应。激动剂mhc肽复合物在活小鼠淋巴结中阻止T细胞迁移数小时，并可导致形成稳定的免疫突触。我们进一步假设趋化动力学和趋化go信号与抗原停止信号之间的竞争对于在初始反应中设置T细胞激活的阈值很重要。例如，我们发现这种停止信号可以通过与显性趋化因子受体CCR7相互作用的趋化因子梯度来逆转，但不能通过与从属趋化因子受体CXCR4相互作用的趋化因子梯度来逆转。我们将通过三个具体目标来检验这两个相互关联的假设。在目的1中，我们将研究淋巴结和脾脏T细胞区偏置随机游走的机制。在目标2中，我们将确定不同形式的激动剂mhc肽复合物对淋巴结中T细胞迁移的影响。在Aim 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.