Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling
Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling
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DOI：
10.1038/nature05269
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发表时间：
2006-12-07
期刊：
影响因子：
64.8
通讯作者：
Palmer, Ed
中科院分区：
文献类型：
--
作者：
Daniels, Mark A.;Teixeiro, Emma;Palmer, Ed
一个健康的个体能够对外源病原体产生免疫应答，同时避免对正常组织的自身免疫攻击。区分自身和非自身的能力被称为“免疫耐受”，对于T淋巴细胞而言，它包括在T细胞个体发育过程中通过阳性选择产生多样的功能性T细胞库，以及通过阴性选择去除明显具有自身反应性的胸腺细胞。为了阐明胸腺细胞是如何做出这些细胞命运决定的，在此我们鉴定出了一些配体，它们界定了一个极其狭窄的区间，该区间跨越了区分阳性选择和阴性选择的阈值。我们表明，在选择阈值处，T细胞抗原受体的配体亲和力的微小增加会导致Ras和丝裂原活化蛋白激酶（MAPK）信号传导中间体的活化及亚细胞定位发生显著变化，并诱导阴性选择。细胞对信号分子进行差异区室化的能力使胸腺细胞能够将模拟输入（亲和力）的微小变化转化为数字输出（阳性选择与阴性选择），并为建立中枢耐受提供了基础。
A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase ( MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input ( affinity) into a digital output ( positive versus negative selection) and provides the basis for establishing central tolerance.