STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms.
Given the association with autoimmune disease, there is great interest in defining cellular factors that limit overactive or misdirected Th17-type inflammation. Using in vivo and in vitro models, we investigated the molecular mechanisms for cytokine-mediated inhibition of Th17 responses, focusing on the role of STAT1 and T-bet in this process. These studies demonstrate that, during systemic inflammation, STAT1- and T-bet-deficient T cells each exhibit a hyper-Th17 phenotype relative to wild-type controls. However, IL-17 production was greater in the absence of T-bet, and when both STAT1 and T-bet were deleted, there was no further increase, with the double-deficient cells instead behaving more like STAT1-deficient counterparts. Similar trends were observed during in vitro priming, with production of Th17-type cytokines greater in T-bet(-/-) T cells than in either STAT1(-/-) or STAT1(-/-) T-bet(-/-) counterparts. The ability of IFN-γ and IL-27 to suppress Th17 responses was reduced in T-bet-deficient cells, and most importantly, ectopic T-bet could suppress signature Th17 gene products, including IL-17A, IL-17F, IL-22, and retinoic acid-related orphan receptor γT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-γ, IL-27, and likely all STAT1-activating cytokines, there are both STAT1 and T-bet-dependent pathways capable of suppressing Th17 responses.
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Alejandro V
AV
Villarino
Eugenio
E
Gallo
Abul K
AK
Abbas
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000502:physiology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007378:Interleukins / Q000502:physiology; D008231:Lymphopenia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation
D016207:Cytokines; C486767:Il27 protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020825:T-Box Domain Proteins; D007371:Interferon-gamma