LFA-1 mediated Costimulation

描述（由申请人提供）：当移动的T细胞遇到ARC时，初始TCR信号传导激活LFA-1，导致形成稳定的T细胞：APC缀合物。这种缀合物的稳定性有助于持续的T细胞信号传导，这是T细胞增殖和效应细胞产生所需的。当稳定的T细胞：APC结合物的形成被破坏时，T细胞仍然可以增殖，这表明T细胞可以暂时整合来自与ARC的多次瞬时相互作用的信号。有趣的是，T细胞：APC相互作用动力学的这些改变与T细胞分化的变化相关，导致耐受性的诱导或Th 1/Th 2效应细胞群平衡的转变。我们已经发现，除了其在T细胞粘附中的重要作用之外，LFA-1还可以调节在T细胞：APC界面处形成的免疫突触内的蛋白质的组织。我们的初步数据表明，LFA-1的能力，直接组织的突触可以调节近端信号事件。与此相反，我们建议，LFA-1调节Th细胞分化的能力可能主要是由粘附和T细胞：APC相互作用的动力学介导的。本申请的总体目标是直接测试LFA-1的这些独立功能如何有助于T细胞活化的幅度和动力学并指导随后的体外和体内T细胞分化。这将通过四个目的来实现：（1）确定LFA如何增强II类定位至cSMAC;（2）确定LFA-1介导的从免疫突触排除CD 45的分子基础和功能影响;（3）鉴定LFA-1介导的Th 2应答下调的分子靶标;和（4）确定LFA-1介导的T细胞动力学变化如何：APC相互作用影响CD 4效应细胞的产生。LFA-1拮抗剂已成功地用于阻断许多有害的免疫应答，但这些试剂在抑制初始T细胞活化、诱导耐受性、调节效应细胞分化或限制活化细胞归巢至炎性位点方面的相对功效尚不清楚。我们的研究将有助于揭示可能有助于LFA-1拮抗剂临床显著免疫调节能力的多种机制。最终，了解决定T细胞免疫应答性质的因素是开发有效和特异性免疫调节剂的关键。

Description (provided by applicant): When mobile T cells encounter an ARC, initial TCR signaling activates LFA-1, leading the formation of a stable T cell:APC conjugate. The stability of this conjugate contributes to the sustained T cell signaling that is required for T cell proliferation and the generation of effector cells. When the formation of stable T cell:APC conjugates is disrupted, T cells can still proliferate, suggesting that T cells can temporally integrate signals derived from multiple transient interactions with ARC. Interestingly, these alterations in the kinetics of T cell:APC interactions correlate with a change in T cell differentiation, leading to the induction of tolerance or a shift in the balance of Th1/Th2 effector cell populations. We have found that in addition to its important role in T cell adhesion, LFA-1 can modulate the organization of proteins within the immunological synapse that forms at the T cell:APC interface. Our preliminary data suggest that the ability of LFA-1 to direct the organization of the synapse can modulate proximal signaling events. In contrast, we propose that the ability of LFA-1 to regulate Th cell differentiation may be mediated primarily by adhesion and the kinetics of T cell:APC interactions. The overall goal of this application is to directly test how these independent functions of LFA-1 contribute to the magnitude and kinetics of T cell activation and directs subsequent T cell differentiation in vitro and in vivo. This will be accomplished through four Aims: (1) Determine how LFA enhances class II localization to the cSMAC; (2) Determine the molecular basis and functional impact of LFA-1-mediated exclusion of CD45 from the immunological synapse; (3) Identify the molecular targets for LFA-1-mediated down regulation of Th2 responses; and (4) Determine how LFA-1-mediated changes in the dynamics of T cell:APC interactions impacts on the generation of CD4 effector cells. LFA-1 antagonists have been used successfully to block many detrimental immune responses, but the relative efficacy of these reagents in inhibiting initial T cell activation, inducing tolerance, modulating effector cell differentiation, or restricting homing of activated cells to inflammatory sites is not clear. Our studies will help unravel the multiple mechanisms that might contribute to the clinically significant immunomodulatory capacity of LFA-1 antagonists. Ultimately, understanding the factors that determine the nature of T cell immune response are key to the development of potent and specific immune modulators.