CD4+ helper T (Th) cells that produce interleukin-17 (IL-17) are a distinct lineage of Th cells (Th17 cells) and are important in autoimmune disorders. Exactly how cytokine signaling generates Th17 cells is only recently becoming clear. IL-6 stimulates Th17 differentiation in vitro, so Yang et al. analyzed splenocytes from immunized wild-type and Il-6 knockout mice by flow cytometry and found that Il-6 knockout mice had the fewest Th17 cells. Interferon-γ (IFN-γ) inhibits Th17 differentiation, so naïve T cells from IFN-γ-deficient mice were activated in vitro with anti-CD3 and anti-CD28 in the presence or absence of cytokines and/or cytokine-neutralizing antibodies. IL-6 simulated production of Th17 cells, whereas IL-23 resulted in few Th17 cells but synergized with IL-6. This effect might be due to the increased amounts of IL-23 receptor (IL-23R) mRNA observed in IL-6-treated naïve CD4+ T cells, as measured by real-time polymerase chain reaction. Infection of naïve CD4+ T cells from IFN-γ-deficient mice with a retrovirus encoding a hyperactive form of signal transducer and activator of transcription-3 (STAT3) resulted in more Th-17 cells and higher amounts of mRNAs for IL-17 and IL-22 than in control cells. Activation of naïve CD4+ T cells from mice with a hematopoietic-specific deletion of Stat3 produced fewer Th17 cells and lower amounts of IL-17 and IL-22 mRNAs than did equivalent treatment of wild-type cells. Activated CD4+ T cells from Stat3 knockout mice had lower amounts of mRNAs for IL-23R and RORγt (retinoic acid receptor-related orphan receptor γ-T), a Th17-specific transcription factor. This study nominates STAT3 as the essential regulator of Th17 cells, analogous to STAT4 and STAT1 in Th1 cells and STAT6 in Th2 cells.
X. O. Yang, A. D. Panopoulos, R. Nurieva, S. H. Chang, D. Wang, S. S. Watowich, C. Dong, STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358-9363 (2007). [Abstract] [Full Text]