An IL-21R STAT hypomorph circumvents functional redundancy in germinal centre responses

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.