A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles
A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles
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DOI：
10.1016/j.immuni.2013.04.008
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发表时间：
2013-06-27
期刊：
影响因子：
32.4
通讯作者：
Sironi, Manuela
中科院分区：
文献类型：
--
作者：
Forni, Diego;Cagliani, Rachele;Sironi, Manuela
T细胞活化在免疫应答和维持自身耐受中起着核心作用。我们分析了T细胞调节分子的进化历史。9个基因参与触发T细胞活化或调节随后的反应在哺乳动物中适应性进化。几个阳性选择的位点与结合伴侣或细胞组分相互作用的位置重叠。人类群体遗传分析揭示了一个复杂的情况下，当地（FASLG，CD 40 LG，HAVCR 2）和世界范围内（FAS，ICOSLG）的适应和H。sapiens-to-Neandertal基因流（种群间的基因转移）。这些基因中的疾病变体是病原体驱动选择的优先靶点，并且细菌驱动选择靶向的克罗恩病风险多态性调节ICOSLG响应于细菌超抗原的表达。因此，我们使用进化信息来产生关于特定遗传变异的功能的实验可检验的假设，并表明对感染的适应是维持自身免疫风险等位基因的基础。
T cell activation plays a central role in immune response and in the maintenance of self-tolerance. We analyzed the evolutionary history of T cell regulatory molecules. Nine genes involved in triggering T cell activation or in regulating the ensuing response evolved adaptively in mammals. Several positively selected sites overlap with positions interacting with the binding partner or with cellular components. Population genetic analysis in humans revealed a complex scenario of local (FASLG, CD40LG, HAVCR2) and worldwide (FAS, ICOSLG) adaptation and H. sapiens-to-Neandertal gene flow (gene transfer between populations). Disease variants in these genes are preferential targets of pathogen-driven selection, and a Crohn's disease risk polymorphism targeted by bacterial-driven selection modulates the expression of ICOSLG in response to a bacterial superantigen. Therefore, we used evolutionary information to generate experimentally testable hypotheses concerning the function of specific genetic variants and indicate that adaptation to infection underlies the maintenance of autoimmune risk alleles.