TCR- independent induction of IL-17 production in TH17 Cells (91.11)

Abstract

Abstract Effector CD4 T cells have been classically divided into two lineages, T-helper type 1 (TH1) and TH2. TH1 cells develop in response to intracellular viruses and bacteria and secrete interferon-γ (IFNγ) while TH2 cells produce interleukin (IL)-4 in response to extracellular pathogens. Recent studies have identified a third distinct lineage of effector CD4 T cells called as TH17 that characteristically produce IL-17. The development of TH17 cells depends on TGFβ and IL-6. The published reports establish a direct link between IL-23 and the TH17 cell subset in mediating inflammatory pathology in certain autoimmune diseases although IL-23 is not required for TH17 commitment. We observed that IL-23 acts synergistically with IL-1 or IL-18 to induce IL-17 cytokine production in TH17 cells independent of T cell receptor (TCR) stimulation, analogous to the induction of IFNγ by IL-12 and IL-18 in TH1 cells. Our results suggest that IL-1 or IL-18 signaling might be preceded by IL-23 signaling through the IL-23 receptor (IL-23R), which is upregulated in TH17 by TGFβ. The TH17 effector function is augmented by these non-antigen-specific responses subsequent to their previous antigen-induced differentiation. Our findings help to delineate the role of IL-23 in TH17 cell biology and identify potential targets for prevention of TH17-mediated immunopathology. This work is supported by the National Institutes of Health (C.T.W.).