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  • Title: Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22, but not interleukin-21, in autoimmune experimental arthritis.
    Author: Mus AM, Cornelissen F, Asmawidjaja PS, van Hamburg JP, Boon L, Hendriks RW, Lubberts E.
    Journal: Arthritis Rheum; 2010 Apr; 62(4):1043-50. PubMed ID: 20131264.
    Abstract:
    OBJECTIVE: To examine the role of interleukin-23 (IL-23) in subgroup polarization of IL-17A-positive and/or interferon-gamma (IFNgamma)-positive T cells in autoimmune disease-prone DBA/1 mice with and without collagen-induced arthritis. METHODS: A magnetic-activated cell sorting system was used to isolate CD4+ T cells from the spleen of naive and type II collagen (CII)-immunized DBA/1 mice. These CD4+ T cells were stimulated in vitro under Th0, Th1, or different Th17 culture conditions. Intracellular staining for IL-17A and IFNgamma was evaluated by flow cytometry. In addition, Th17 cytokines and T helper-specific transcription factors were analyzed by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. RESULTS: In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor gammat (RORgammat), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression. In contrast, transforming growth factor beta1 (TGFbeta1)/IL-6 was a potent inducer of RORgammat, RORalpha, IL-17A, IL-17F, IL-21, and FoxP3 in these cells. In contrast to TGFbeta1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice. Consistent with these findings, IL-23 showed a more pronounced induction of the IL-17A+IFNgamma- subset in CD4+ T cells from CII-immunized mice. However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFbeta1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice. CONCLUSION: IL-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of IL-22, but not IL-21, levels in autoimmune arthritis. These data indicate different mechanisms for IL-23 and TGFbeta1/IL-6 at the transcription factor level during Th17 differentiation in autoimmune experimental arthritis.
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