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Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages

Abstract

CD4+ T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (TH1) or TH2 lineages and instead favor the idea of a distinct effector lineage we call 'TH-17'. The development of TH-17 cells from naive precursor cells was potently inhibited by interferon-γ (IFN-γ) and IL-4, whereas committed TH-17 cells were resistant to suppression by TH1 or TH2 cytokines. In the absence of IFN-γ and IL-4, IL-23 induced naive precursor cells to differentiate into TH-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-γ signaling enhances development of pathogenic TH-17 effector cells that can exacerbate autoimmunity.

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Figure 1: TH1 and TH2 cells are poorly responsive to IL-23.
Figure 2: IFN-γ inhibits the development of IL-17-producing effector CD4+ T cells.
Figure 3: Differentiation of IL-17-producing effector cells from naive CD4+ T cells.
Figure 4: Both type I and type II interferons inhibit the development of IL-17-producing effector cells.
Figure 5: The development of IL-17 effector cells is independent of STAT1 and T-bet.
Figure 6: Differential expression of IL-12R and IL-23R by TH1- and TH-17-polarized effector populations.
Figure 7: IL-4 suppresses TH-17 cell development independently of IFN-γ.
Figure 8: STAT4 and STAT6 signaling are dispensable for TH-17 cell development.
Figure 9: Committed TH-17 effector cells have a stable phenotype.

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Acknowledgements

We thank W. Ouyang and N. Ghilardi, and members of the Weaver laboratory for comments and suggestions. Supported by the National Institutes of Health (AI035783, AI057956 and DK64400 to C.T.W.), Sankyo (C.T.W.), Howard Hughes Medical Institute (K.M.M.) and the National Multiple Sclerosis Society (L.E.H.).

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Correspondence to Casey T Weaver.

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Supplementary Fig. 1

IL-23 does not promote IFN-γ production by CD4+ T cells. (PDF 449 kb)

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Harrington, L., Hatton, R., Mangan, P. et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6, 1123–1132 (2005). https://doi.org/10.1038/ni1254

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