STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and-independent mechanisms

Alejandro V. Villarino, Eugenio Gallo, Abul K. Abbas

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)6461-6471
Number of pages11
JournalJournal of Immunology
Issue number11
StatePublished - Dec 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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