Signaling Cascades in Humoral Immunity and Autoimmunity

描述（由申请方提供）：有效的免疫应答需要外周CD 4 + T细胞的适当活化和分化。这些过程之后需要及时消除应答T细胞，以恢复T细胞稳态。T细胞活化、扩增和存活的适当调节的缺陷是许多自身免疫性疾病的发病机制的基础。T细胞用来正确控制这些过程并防止自身免疫发作的分子机制尚未完全阐明。该提案的重点是一种名为IBP的新型蛋白质。IBP表现出与SWAP-70的显著同源性，SWAP-70是Rho GTP酶的新型激活剂。IBP是T细胞中表达的这种新型蛋白质家族的唯一成员。我们的实验室先前已经表明，在TCR接合后，IBP被募集到免疫突触并激活Rho GTP酶。有趣的是，随着年龄的增长，缺乏IBP的小鼠会出现狼疮样综合征。我们最近产生了TCR转基因（DO11.10）IBP缺陷小鼠。这些小鼠迅速发展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学与中枢耐受性的损害无关，而是伴随着外周CD 4 + T细胞隔室内的三种主要异常：对低水平刺激的高反应性、TH效应器功能的不适当获得和活化T细胞的消除受损。综上所述，这些发现使我们假设IBP是一种新的T细胞活化和稳态调节剂，对于预防自身免疫性病理生理学至关重要。本提案的总体目标是获得对IBP在T细胞功能和稳态中的作用的机械理解。具体而言，我们将：1）剖析IBP调节CD 4 + T细胞区分TCR连接效力的能力的机制，2）研究IBP用于控制T细胞效应子功能的途径，和3）确定IBP用于调节T细胞存活的机制。相关性：该提案侧重于剖析一种新分子IBP在自身免疫中的作用。小鼠中缺乏IBP导致自身免疫的自发发展。这一提议将为负责维持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.