Signaling Cascades in Humoral Immunity and Autoimmunity

描述（由申请人提供）：有效的免疫应答需要外周血CD4+ T细胞的适当激活和分化。这些过程需要及时消除应答的T细胞，以恢复T细胞的稳态。T细胞活化、扩增和存活的适当调节缺陷是许多自身免疫性疾病发病机制的基础。T细胞用来适当控制这些过程和防止自身免疫发生的分子机制尚未完全阐明。本研究的重点是一种名为IBP的新型蛋白质。IBP与SWAP-70具有显著的同源性，SWAP-70是一种新型的Rho GTPases激活剂。IBP是这个在T细胞中表达的新蛋白家族的唯一成员。我们的实验室先前已经证明，在TCR参与后，IBP被招募到免疫突触并激活Rho gtpase。有趣的是，IBP缺乏的小鼠随着年龄的增长，会患上类似狼疮的综合症。我们最近培育了TCR转基因（DO11.10） IBP缺陷小鼠。这些小鼠迅速发展为自身免疫性关节炎和血管炎。在没有IBP的情况下观察到的病理生理与中枢耐受性的损害无关，而是伴随着外周CD4+ T细胞室的三种主要异常：对低水平刺激的高反应性，TH效应功能的不适当获取，以及活化T细胞的消除受损。综上所述，这些发现使我们假设IBP是T细胞激活和稳态的一种新的调节剂，对自身免疫病理生理的预防至关重要。本建议的总体目标是获得IBP在T细胞功能和体内平衡中的作用的机制理解。具体来说，我们将：1)剖析IBP调节CD4+ T细胞辨别TCR连接效力的机制，2)研究IBP控制T细胞效应功能的途径，以及3)确定IBP调节T细胞存活的机制。相关性：本提案的重点是剖析一种新分子IBP在自身免疫中的作用。小鼠缺乏IBP可导致自身免疫的自发发展。这一建议将为维持T细胞耐受性的分子网络提供新的见解。这些知识对于开发针对自身免疫性疾病的新策略至关重要。

DESCRIPTION (provided by applicant): Effective immune responses require the appropriate activation and differentiation of peripheral CD4+ T cells. These processes need to be followed by the timely elimination of the responding T cells in order to restore T cell homeostasis. Defects in the appropriate regulation of T cell activation, expansion, and survival underlie the pathogenesis of many autoimmune disorders. The molecular machinery employed by T cells to properly control these processes and prevent the onset of autoimmunity has not been fully elucidated. This proposal focuses on a novel protein termed IBP. IBP exhibits significant homology to SWAP-70, a novel type of activator for Rho GTPases. IBP is the only member of this novel family of proteins expressed in T cells. Our laboratory has previously shown that, upon TCR engagement, IBP is recruited to the immunological synapse and activates Rho GTPases. Interestingly, mice deficient in IBP develop, with age, a lupus-like syndrome. We have recently generated TCR transgenic (DO11.10) IBP deficient mice. These mice rapidly develop autoimmune arthritis and vasculitis. The pathophysiology observed in the absence of IBP is not associated with impairments in central tolerance but is instead accompanied by three major abnormalities within the peripheral CD4+ T cell compartment: hyperresponsiveness to low-levels of stimulation, inappropriate acquisition of TH effector functions, and impaired elimination of activated T cells. Taken all together, these findings have led us to hypothesize that IBP is a novel regulator of T cell activation and homeostasis that is critical for the prevention of autoimmune pathophysiology. The overall goal of this proposal is to gain a mechanistic understanding of the role of IBP in T cell function and homeostasis. Specifically, we will: 1) Dissect the mechanisms by which IBP regulates the ability of CD4+ T cells to discriminate the potency of TCR ligation, 2) Investigate the pathways employed by IBP to control T cell effector function, and 3) Ascertain the mechanisms used by IBP to regulate T cell survival. Relevance: This proposal focuses on dissecting the role of a novel molecule, IBP, in autoimmunity. Lack of IBP in mice leads to the spontaneous development of autoimmunity. This proposal will shed novel insights into the molecular networks responsible for the maintenance of T cell tolerance. This knowledge will be critical for the development of novel strategies aimed at targeting autoimmune diseases.