IL-2-induced Stat3 Signaling is Critical for Effector Treg Cell Programming

Dean, E. C.; DiToro, D. F.; Pham, D.; Gao, M.; Frey, B. F.; Harbour, S. N.; Figge, D. A.; Miller, A. T.; Glassman, C. R.; Garcia, K. C.; Hatton, R. D.; Weaver, C.

doi:10.1101/2023.09.26.559434

bioRxiv · 10.1101/2023.09.26.559434

IL-2-induced Stat3 Signaling is Critical for Effector Treg Cell Programming

Dean, E. C.·DiToro, D. F.·Pham, D.·Gao, M.·Frey, B. F.·Harbour, S. N.·Figge, D. A.·Miller, A. T.·Glassman, C. R.·Garcia, K. C.·Hatton, R. D.·Weaver, C.

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Abstract

Maintenance of immune homeostasis to the intestinal mictrobiota is dependent on a population of effector regulatory T (eTreg) cells that develop from microbiota-reactive induced (i)Treg cells. A cardinal feature of eTreg cells is their production of IL-10, which plays a non-redundant role in immune tolerance of commensal microbes. Here, we identify an unexpected role for IL-2-induced Stat3 signaling to program iTreg cells for eTreg cell differentiation and Il10 transcriptional competency. IL-2 proved to be both necessary and sufficient for eTreg cell development - contingent on Stat3 output of the IL-2 receptor coordinate with IL-2 signaling during early Treg cell commitment. Induction of iTreg cell programming in absence of IL-2-induced Stat3 signaling resulted in impaired eTreg cell differentiation and a failure to produce IL-10. An IL-2 mutein with reduced affinity for the IL-2R{gamma} ({gamma}c) chain was found to have blunted IL-2R Stat3 output, resulting in a deficiency of Il10 transcriptional programming that could not be fully rescued by Stat3 signaling subsequent to an initial window of iTreg cell differentiation. These findings expose a heretofore unappreciated role of IL-2 signaling that acts early to program subsequent production of IL-10 by developing eTreg cells, with broad implications for IL-2-based therapeutic interventions in immune-mediated diseases.

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Dean, E. C., DiToro, D. F., Pham, D., Gao, M., Frey, B. F., Harbour, S. N., Figge, D. A., Miller, A. T., Glassman, C. R., Garcia, K. C., Hatton, R. D., Weaver, C.. 2023-09-28. IL-2-induced Stat3 Signaling is Critical for Effector Treg Cell Programming. https://doi.org/10.1101/2023.09.26.559434

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