Sensitivity of T cells to antigen and antagonism emerges from differential regulation of the same molecular signaling module.
Sensitivity of T cells to antigen and antagonism emerges from differential regulation of the same molecular signaling module.
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T 细胞对抗原和拮抗的敏感性源于同一分子信号传导模块的差异调节。
DOI：
10.1073/pnas.0611482104
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发表时间：
2007
影响因子：
11.1
通讯作者：
Chakraborty,ArupK
中科院分区：
文献类型：
--
作者：
Wylie,DennisC;Das,Jayajit;Chakraborty,ArupK
T辅助细胞的激活是对病原体的适应性免疫反应所必需的，而虚假的激活可导致器官特异性自身免疫(如多发性硬化症)。T细胞活化是由T细胞表面表达的T细胞受体与抗原提呈细胞表面的主要组织相容性复合体(PMHC)分子结合而产生的膜-近端信号。这些信号过程调节不同的结果，例如T细胞敏感地区分刺激性pMHC分子和那些具有“自我”特征的pMHC分子的能力，以及拮抗现象(其中某些pMHC分子的存在损害T细胞受体信号)。我们描述了T细胞膜-近端信号的分子模型，从该模型中，这些不同的观察结果出现在同一枚硬币的两面。如果没有对相关生化事件的随机性质的明确考虑，这种与不同数据一致的统一机制的发展是不可能的。我们的研究还表明，以前提出的某些概念并不是决斗的想法，而是膜-近端信号的统一分子模型的不同刺激依赖的表现形式。这一模型可能为进一步研究调节T细胞对自身和外来抗原的激活的早期事件以及开发抑制异常信号的干预方案提供一个概念性的框架。
Activation of T helper cells is necessary for the adaptive immune response to pathogens, and spurious activation can result in organ-specific autoimmunity (e.g., multiple sclerosis). T cell activation is initiated by membrane-proximal signaling that is predicated on the binding of the T cell receptor expressed on the T cell surface to peptide major histocompatibility complex (pMHC) molecules presented on the surface of antigen-presenting cells. These signaling processes regulate diverse outcomes, such as the ability of T cells to discriminate sensitively between stimulatory pMHC molecules and those that are characteristic of “self,” and the phenomenon of antagonism (wherein the presence of certain pMHC molecules impairs T cell receptor signaling). We describe a molecular model for membrane-proximal signaling in T cells from which these disparate observations emerge as two sides of the same coin. This development of a unified mechanism that is consistent with diverse data would not have been possible without explicit consideration of the stochastic nature of the pertinent biochemical events. Our studies also reveal that certain previously proposed concepts are not dueling ideas but rather are different stimuli-dependent manifestations of a unified molecular model for membrane-proximal signaling. This model may provide a conceptual framework for further investigations of early events that regulate T cell activation in response to self and foreign antigens and for the development of intervention protocols to inhibit aberrant signaling.