An IL-21R hypomorph circumvents functional redundancy to define STAT1 signaling in germinal center responses

Jandl, C.; Warren, J.; Owens, S.; Batten, M.; Wang, H.; King, C.

doi:10.1101/2025.11.14.688418

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bioRxiv · 10.1101/2025.11.14.688418

An IL-21R hypomorph circumvents functional redundancy to define STAT1 signaling in germinal center responses

Jandl, C.·Warren, J.·Owens, S.·Batten, M.·Wang, H.·King, C.

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Abstract

Interleukin-21 receptor engagement initiates a Janus Kinase (JAK) - signal transducer and activator of transcription (STAT) signalling cascade that activates several STAT proteins that drive the germinal center response. However, the relative effects of IL-21 on individual STAT proteins during the differentiation of T follicular helper cells and germinal center B cells has been difficult to distinguish. Here, we characterise a novel mutation in the interleukin-21 receptor (IL-21REINS) that creates a unique defect in the activation of STAT1. Our findings provide evidence that IL-21 mediated activation of STAT1 has a nonredundant role in the differentiation of T follicular (Tfh) cells following T dependent immunisation. IL-21REINS 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.

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Jandl, C., Warren, J., Owens, S., Batten, M., Wang, H., King, C.. 2025-11-14. An IL-21R hypomorph circumvents functional redundancy to define STAT1 signaling in germinal center responses. https://doi.org/10.1101/2025.11.14.688418

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