TGFβ Plays a Minimal Role in Supporting Th17 Cell Phenotype Post Differentiation

ABSTRACT Th17 cells can adopt different functional capabilities in response to environmental stimuli, exhibiting functional plasticity, contributing to both pathogenic autoinflammation but also vital homeostatic immune regulation, particularly at mucosal barriers. However, the upstream signals regulating Th17 cell plasticity and stability remain to be fully outlined. Here, we examined whether the cytokine TGFβ contributed to Th17 cell functional capabilities following differentiation. We utilized an IL‐17A‐specific cre to delete TGFβ receptor II in IL‐17‐producing cells, alongside fate‐mapping cre‐positive cells, to ascertain the role of TGFβ in supporting Th17 cell activity. TGFβR‐deficient Th17 cells were expanded at both mucosal barriers and within lymphoid tissues. However, contrasting previous studies, we show that in both steady state and following induction of inflammation, TGFβR‐deficient Th17 cells remain incredibly stable. We show that TGFβR‐deficient Th17 cells still predominantly produce IL‐17A, express the canonical Th17 cell transcription factor RORγt, and exhibit no altered capacity to produce additional cytokines, indicating TGFβ plays a redundant role in limiting or tailoring the activity of differentiated Th17 cells. However, upon transfer into a lymphopenic environment, TGFβR‐deficient Th17 cells exhibit substantive instability compared to TGFβR‐sufficient control cells, dramatically increasing IFNγ and reducing IL‐17A production, transdifferentiating into Th1‐like exTh17 cells. Thus, our data provide crucial insights into the importance of TGFβ in tailoring Th17 cells, refining our understanding to demonstrate that in lymphocyte‐replete hosts, even in the presence of inflammatory signals, TGFβ plays a limited role in maintaining Th17 cell phenotypes.