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Negative Regulation of TCR Signaling in Immunological Tolerance: Taming Good and Evil

机译：TCR信号在免疫耐受中的负调控：驯服善恶

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摘要

To prevent the occurrence and expansion of autoreactive T cell clones, and hence the development of autoimmunendisease (such as multiple sclerosis, rheumatoid arthritis, lupus erythematosus, and diabetes), the healthy immunensystem is equipped with a variety of immunological mechanisms, summarized as self-tolerance. The strength and frequencynof the T cell receptor (TCR) signal as well as the costimulatory context critically control T cell fate and the compositionnof the T cell repertoire at different stages of lymphoid development. Central tolerance mechanisms in the thymusncause developing T cells with high affinity for self-peptide-MHC to undergo clonal deletion via programmed cell deathn(apoptosis) in a process referred to as negative selection. In contrast, T cells with a weak affinity are positively selected or,nif the signal is just below the deletional threshold, enter a pathway to become regulatory T cells (Treg). Peripheral toleranceninvolves functional inactivation (“anergy”), suppression or extrathymic clonal deletion of autoreactive T cells thatnhave escaped negative selection. The activation thresholds of TCR- and costimulatory-signaling pathways are modified byndifferent groups of negative regulatory proteins with distinct developmentally regulated expression/activation patterns andnfunctional mechanisms. This review provides an overview of the key negative regulators of T cell receptor signaling, includingnthe Cbl family of ubiquitin ligases, phosphatases, the Dok family of adaptor proteins, as well as the serinethreoninenkinase Drak2, and compares their differential impact on central and peripheral tolerance mechanisms, includingnclonal deletion, anergy and Treg suppression. Furthermore, the impact of targeting the related genes in mice on the susceptibilitynto different autoimmune diseases as well as the therapeutic potential of developing specific and effective immunentreatments that modify these negative regulators of TCR signaling are explored.
机译：为了防止自身反应性T细胞克隆的发生和扩展，从而防止自身免疫病（例如多发性硬化症，类风湿性关节炎，红斑狼疮和糖尿病）的发生，健康的免疫系统配备了多种免疫机制，总结为自我免疫公差。 T细胞受体（TCR）信号的强度和频率以及共刺激的环境在淋巴样发育的不同阶段严格控制T细胞的命运和T细胞组成的组成。胸腺的中枢耐受机制导致发育中的T细胞对自身肽MHC具有高亲和力，并通过程序性细胞死亡（细胞凋亡）经历克隆删除，此过程称为阴性选择。相反，积极选择亲和力较弱的T细胞，或者，如果信号刚好在缺失阈值以下，则进入成为调节性T细胞（Treg）的途径。外周耐受涉及已逃避阴性选择的自身反应性T细胞的功能失活（“无能”），抑制或胸腺外克隆性删除。 TCR和共刺激信号通路的激活阈值由不同组的负调控蛋白修饰，这些蛋白具有不同的发育调控的表达/激活模式和功能机制。这篇综述概述了T细胞受体信号转导的关键负调控因子，包括遍在蛋白连接酶的Cbl家族，磷酸酶，Dok衔接蛋白家族以及丝氨酸苏氨酸激酶Drak2，并比较了它们对中枢和外周耐受机制的不同影响。 ，包括肺部缺失，无能和抑制Treg。此外，探索了以小鼠中的相关基因为靶标对不同的自身免疫疾病易感性的影响，以及开发修饰这些TCR信号负调控因子的特异性和有效免疫疗法的治疗潜力。

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