Abstract
T cells that produce both IL-17 and IFN-γ, and co-express ROR-γt and T-bet, are often found at sites of autoimmune inflammation. However, it is unknown whether this co-expression of T-bet with ROR-γt is a prerequisite for immunopathology. We show here that T-bet is not required for the development of Th17-driven experimental autoimmune encephalomyelitis (EAE). The disease was not impaired in T-bet−/− mice and was associated with low IFN-γ production and elevated IL-17 production among central nervous system (CNS) infiltrating CD4+ T cells. T-bet−/− Th17 cells generated in the presence of IL-6/TGF-β/IL-1 and IL-23 produced GM-CSF and high levels of IL-17 and induced disease upon transfer to naïve mice. Unlike their WT counterparts, these T-bet−/– Th17 cells did not exhibit an IL-17→IFN-γ switch upon reencounter with antigen in the CNS, indicating that this functional change is not critical to disease development. In contrast, T-bet was absolutely required for the pathogenicity of myelin-responsive Th1 cells. T-bet-deficient Th1 cells failed to accumulate in the CNS upon transfer, despite being able to produce GM-CSF. Therefore, T-bet is essential for establishing Th1-mediated inflammation but is not required to drive IL-23-induced GM-CSF production, or Th17-mediated autoimmune inflammation.
Highlights
An illuminating series of studies over the past 5 years has led to the appreciation that, far from being members of categorically fixed subsets, CD4+ T cells can switch their expression of transcription factors and downstream effector functions including cytokines, dependent on the inflammatory environment theyC 2013 The Authors
In which Th1 cells are generated from naıve myelin basic protein (MBP) responsive Tg4 TCR transgenic T cells by MBP peptide stimulation in the presence of IL-12 and IL-18 (Fig. 2I), we found that passive EAE was dependent on expression of T-bet in the transferred T cells (Fig. 2J)
We have found no evidence for an impairment of proliferative capacity in T-bet−/− T cells, so we believe that the absence of transferred T-bet−/− Th1 cells from the central nervous system (CNS) most likely reflects a failure in migration
Summary
An illuminating series of studies over the past 5 years has led to the appreciation that, far from being members of categorically fixed subsets, CD4+ T cells can switch their expression of transcription factors and downstream effector functions including cytokines, dependent on the inflammatory environment theyC 2013 The Authors. T-bet has been reported to be essential for EAE [7], even in passive transfer models involving administration of myelin-reactive Th17 cells [8]. This paradox has been resolved by elegant fate-mapping studies that revealed that the majority IFN-γ+ and T-bet+ T cells in the CNS have previously expressed, but since extinguished, IL-17 [9, 10]
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