An IL-21R STAT hypomorph circumvents functional redundancy in germinal centre responses.
- 1Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, Australia.
- 2School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
Abstract
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-21REINS) 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-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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BibTeX
@article{jandl2026il21r,
title = {{An IL-21R STAT hypomorph circumvents functional redundancy in germinal centre responses.}},
author = {Christoph Jandl and Joanna Warren and Samantha Owens and Marcel Batten and Howard Wang and Cecile King},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.109834},
url = {https://europepmc.org/article/MED/42909478},
note = {CC BY},
}
RIS
TY - JOUR
TI - An IL-21R STAT hypomorph circumvents functional redundancy in germinal centre responses.
AU - Christoph Jandl
AU - Joanna Warren
AU - Samantha Owens
AU - Marcel Batten
AU - Howard Wang
AU - Cecile King
PY - 2026
DA - 2026/10/23
JO - ELife
DO - 10.7554/elife.109834
UR - https://europepmc.org/article/MED/42909478
AB - 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-21REINS) 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-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.
SN - 2050-084X
ER -