UPMC Researchers Publish Work on How STAT3 Maintains the Th17 Effector Phenotype

Physicians and researchers from the UPMC Division of Rheumatology and Clinical Immunology have published, “Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen” in the Journal of Experimental Medicine.

Type 17 helper T cells are important for defending against pathogens and maintaining barriers; however, they have also been shown to promote some autoimmune diseases. STAT3 is a transcription factor that is necessary for the development of this cell type, but its function after cell differentiation is unknown. The team showed that maintaining STAT3 expression in Th17 cells is necessary for full induction of CNS inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Without maintained STAT3 expression, Th17 cells are reduced in lymph nodes, blood, and CNS during EAE.

After STAT3 deletion, Th17 cells have reduction in cell proliferation but not apoptosis. STAT1, which has known antiproliferative effects, is upregulated and is more readily phosphorylated in response to IL-6 and IL-23 in Th17 cells that do not maintain STAT3 expression.

Th17s without maintained STAT3 lack the capacity to produce proinflammatory cytokines in response to cognate antigen, while cytokine production is preserved with PMA and ionomycin stimulation, suggesting a nontranscriptional effect of STAT3.

Mitochondrial membrane potential was reduced in STAT3-deleted Th17s compared to STAT3-sufficient Th17s and this effect was recapitulated using a STAT3 inhibitor.

Blockade of mitochondrial calcium export resulted in diminished cytokine production in response to antigen, similar to that of STAT3 deletion. Antigen stimulation with addition of ionomycin, which releases calcium stores, rescued the cytokine defects of STAT3 deficient Th17 cells.

The data reveal novel roles for STAT3 beyond transcriptional control in maintaining Th17 effector function including proliferation, competitive regulation of STAT1, maintenance of mitochondrial membrane potential, and enhancement of TCR/antigen-induced cytokine production. Inhibition of STAT3 activation by medications that target the Jak-STAT pathways during the treatment of autoimmune disease may act to dampen Th17 responsiveness through these mechanisms, thereby preventing inappropriate inflammation.

Authors include: Catherine H. Poholek MD, PhD, Itay Raphael, PhD, Dongwen Wu, Shankar Revu, MSc, PhD, Natalie Rittenhouse, Uzodinma U. Uche, Saikat Majumder, Lawrence P. Kane, PhD, Amanda C. Poholek, PhD, and Mandy J. McGeachy, PhD, all of the University of Pittsburgh.

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