| First Author | Villarino AV | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 11 | Pages | 6461-71 |
| PubMed ID | 20974984 | Mgi Jnum | J:167369 |
| Mgi Id | MGI:4868139 | Doi | 10.4049/jimmunol.1001343 |
| Citation | Villarino AV, et al. (2010) STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J Immunol 185(11):6461-71 |
| abstractText | 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-gamma 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 gammaT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-gamma, IL-27, and likely all STAT1-activating cytokines, there are both STAT1 and T-bet-dependent pathways capable of suppressing Th17 responses. |
