IL-21R STAT 亚效突变体规避生发中心反应中的功能冗余
An IL-21R STAT hypomorph circumvents functional redundancy in germinal centre responses
一种新型 IL-21R EINS 突变可造成 STAT1 激活的显性缺陷，从而绕开生发中心反应中的功能冗余。IL-21 通过 JAK–STAT 级联激活多个 STAT 蛋白驱动生发中心反应，但各 STAT 蛋白的相对作用此前难以区分。研究发现，IL-21 介导的 STAT1 激活在 T 细胞依赖性免疫后 Tfh 细胞分化中具有非冗余作用；IL-21R EINS 的 Tfh 细胞损伤程度甚至超过 IL-21R 基因缺陷的 Tfh 细胞，对基于蛋白敲除小鼠得出的 IL-21 功能认识提出质疑。该结果表明，IL-21R 亚效突变体存在时功能补偿失效，提示潜在补偿机制会影响对复杂生物系统的解读。
来源：eLife · doi.org
Interleukin-21 receptor engagement initiates a Janus kinase–signal transducer and activator of transcription (STAT) signalling cascade that activates several STAT proteins that drive the germinal centre (GC) response. However, the relative effects of IL-21 on individual STAT proteins during the differentiation of T follicular helper (Tfh) cells and GC B cells has been difficult to distinguish. Here, we characterize a novel mutation in the interleukin-21 receptor (IL-21R EINS ) that creates a dominant defect in the activation of STAT1. Our findings provide evidence that IL-21-mediated activation of STAT1 has a non-redundant role in the differentiation of Tfh cells following T-dependent immunization. IL-21R EINS Tfh cells were even more impaired than Tfh cells genetically deficient in IL-21R, questioning our current understanding of the role of IL-21 derived from protein knockout mice. The observation that functional compensation fails in the presence of the IL-21R hypomorph provides insight into how underlying compensation can impact our interpretation of a complex biological system.