title: STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis.
abstract: STAT3 regulates CD4+ T cell survival and differentiation. However, its effects on CD8+ T cells are not well understood. Here, we show that in comparison to WT CD8+ T cells, STAT3-deficient CD8+ T cells exhibit a preactivated memory-like phenotype, produce more IL-2, proliferate faster, and are more sensitive to activation-induced cell death (AICD). The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors (FoxO1, FoxO3A), p21(waf1), p27(KIP1), Bcl-2, OX-40, and upregulation of FasL, Bax, and Bad. We examined whether STAT3-deficient CD8+ T cells can mount effective response during herpes simplex virus (HSV-1) infection and experimental autoimmune uveitis (EAU). Compared to WT mice, HSV-1-infected STAT3-deficient mice (STAT3KO) produced less IFN-γ and virus-specific KLRG-1+ CD8+ T cells. STAT3KO mice are also resistant to EAU and produced less IL-17-producing Tc17 cells. Resistance of STAT3KO to EAU correlated with marked expansion of IL-10-producing regulatory CD8+ T cells (CD8-Treg) implicated in recovery from autoimmune encephalomyelitis. Thus, increases of IL-6-induced STAT3 activation observed during inflammation may inhibit expansion of CD8-Tregs, thereby impeding recovery from uveitis. These results suggest that STAT3 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of STAT3 as treatment for uveitis, derived, in part, from promoting CD8-Treg expansion.
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Allergy and Viral Diseases, National Institutes of Health, Building 10, Room 10N109A, 10 Center Drive, Bethesda, MD 20892-1857, USA.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.forename: Ivy M
authors.initials: IM
authors.lastname: Dambuza
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Lee
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Frank
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D049109:Cell Proliferation; D002469:Cell Separation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006561:Herpes Simplex / Q000378:metabolism* / Q000821:virology; D018259:Herpesvirus 1, Human; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D014605:Uveitis / Q000276:immunology* / Q000821:virology
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10