Roquin Differentiates the Specialized Functions of Duplicated T Cell Costimulatory Receptor Genes Cd28 and Icos
Roquin Differentiates the Specialized Functions of Duplicated T Cell Costimulatory Receptor Genes Cd28 and Icos
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DOI：
10.1016/j.immuni.2008.12.015
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发表时间：
2009-02-20
期刊：
影响因子：
32.4
通讯作者：
Vinuesa, Carola G.
中科院分区：
文献类型：
--
作者：
Linterman, Michelle A.;Rigby, Robert J.;Vinuesa, Carola G.
在免疫系统的进化适应过程中，宿主防御与自身反应之间进行了权衡。通过共刺激受体CD28产生的信号使T细胞对病原体产生特异性反应，而通过相关的共刺激受体ICOS产生的信号对亲和力成熟和记忆抗体反应至关重要。ICOS配体与病原体诱导的CD28配体不同，在免疫系统中广泛和结构性地表达。在这里，我们表明，这两个通路之间的串扰提供了一种机制，以消除正常的T细胞对CD28的依赖。当E3泛素连接酶Roquin突变时，CD28介导的几种反应-毛囊辅助T细胞的产生、生发中心的形成、T辅助1细胞对沙门氏菌的毛囊外抗体反应和细菌清除，以及调节性T细胞的稳态-变得独立于CD28而依赖于ICOS。因此，从功能上区分ICOS和CD28信号的机制对于正常免疫反应的双信号控制至关重要。
During evolutionary adaptation in the immune system, host defense is traded off against autoreactivity. Signals through the costimulatory receptor CD28 enable T cells to respond specifically to pathogens, whereas those through the related costimulatory receptor, ICOS, which arose by gene duplication, are critical for affinity maturation and memory antibody responses. ICOS ligand, unlike the pathogen-inducible CD28 ligands, is widely and constitutively expressed in the immune system. Here, we show that crosstalk between these two pathways provides a mechanism for obviating the normal T cell dependence on CD28. Several CD28-mediated responses-generation of follicular helper T cells, germinal center formation, T helper 1 cell-dependent extrafollicular antibody responses to Salmonella and bacterial clearance, and regulatory T cell homeostasis-became independent of CD28 and dependent on ICOS when the E3 ubiquitin ligase Roquin was mutated. Mechanisms to functionally compartmentalize ICOS and CD28 signals are thus critical for two-signal control of normal immune reactions.