IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms
- PMID: 14657353
- PMCID: PMC299900
- DOI: 10.1073/pnas.2536517100
IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms
Abstract
IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells, signals through the T cell cytokine receptor (TCCR)/WSX-1 expressed on naïve CD4+ T cells and natural killer cells. TCCR/WSX-1 deficiency results in delayed T helper type 1 (TH1) development through an unresolved mechanism. We report here that IL-27 stimulation in developing murine T helper cells potently induces the expression of the major TH1-specific transcription factor T-bet and its downstream target IL-12R beta2, independently of IFN gamma. In addition, IL-27 suppresses basal expression of GATA-3, the critical TH2-specific transcription factor that inhibits TH1 development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1 induces phosphorylation of Stat1, Stat3, Stat4, and Stat5. Stat1 is required for suppression of GATA-3, but T-bet induction by IL-27 can also be mediated through a Stat1-independent pathway. Despite its TH1-like signaling profile, IL-27 is not sufficient to drive the differentiation of CD4+ T cells into IFN gamma-producing cells. Similarly, IL-27 induces T-bet expression in primary natural killer cells, but this does not result in an increase of IFN gamma production or cytotoxic activity. Therefore, although IL-27 is unable to drive IFN gamma production on its own, it plays an important role in the early steps of TH1 commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.
Figures
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References
-
- Abbas, A. K., Murphy, K. M. & Sher, A. (1996) Nature 383, 787-793. - PubMed
-
- Mosmann, T. R. & Sad, S. (1996) Immunol. Today 17, 138-146. - PubMed
-
- O'Garra, A. (1998) Immunity 8, 275-283. - PubMed
-
- Murphy, K. M. & Reiner, S. L. (2002) Nat. Rev. Immunol. 2, 933-944. - PubMed
-
- Wurster, A. L., Tanaka, T. & Grusby, M. J. (2000) Oncogene 19, 2577-2584. - PubMed
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