Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen.

The Journal of Experimental Medicine
Catherine H PoholekMandy J McGeachy

Abstract

The STAT3 signaling pathway is required for early Th17 cell development, and therapies targeting this pathway are used for autoimmune disease. However, the role of STAT3 in maintaining inflammatory effector Th17 cell function has been unexplored. Th17ΔSTAT3 mice, which delete STAT3 in effector Th17 cells, were resistant to experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Th17 cell numbers declined after STAT3 deletion, corresponding to reduced cell cycle. Th17ΔSTAT3 cells had increased IL-6-mediated phosphorylation of STAT1, known to have antiproliferative functions. Th17ΔSTAT3 cells also had reduced mitochondrial membrane potential, which can regulate intracellular Ca2+. Accordingly, Th17ΔSTAT3 cells had reduced production of proinflammatory cytokines when stimulated with myelin antigen but normal production of cytokines when TCR-induced Ca2+ flux was bypassed with ionomycin. Thus, early transcriptional roles of STAT3 in developing Th17 cells are later complimented by noncanonical STAT3 functions that sustain pathogenic Th17 cell proliferation and cytokine production.

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Citations

Jan 28, 2021·Cancers·Alexander OuAmy B Heimberger
Feb 13, 2021·Annual Review of Immunology·Saikat Majumder, Mandy J McGeachy
Jun 22, 2021·International Reviews of Immunology·Kevin M HarrisLinda R Watkins
Jul 3, 2021·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Liang WangDapeng Chen
Aug 19, 2021·Accounts of Chemical Research·Phei Er SawSangyong Jon
Aug 6, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·D Alejandro CanariaMatthew R Olson

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