TL1A, a TNF-like molecule, regulates the differentiation of human TH17 cells (133.21)

Abstract TL1A is a member of the TNF superfamily that mediates a strong co-stimulation of TH1 cells by enhancing IFN-γ production by CD4+ T cells. The expression of TL1A is increased in inflamed mucosa of Crohn's Disease patients and in murine models of ileitis. We have shown that TL1A is induced in human antigen-presenting cells (APCs) by Fc γ Receptor but not TLR signaling. Furthermore, neutralizing TL1A antibodies attenuate colitis by attenuating TH1 and TH17 responses in a chronic model of colitis. However, it remains to be elucidated if TL1A enhances de novo differentiation of TH17 cells. Here we demonstrate that FcγR signaling in APCs leads to the concomitant induction of TL1A, IL-6, TGF-β, and IL-23. TL1A, in combination with TGF-β and IL-6, promotes the differentiation of human TH17 cells from naive CD4+ T cells and leads to a unique cell population of IL-17/IFN-γ producing TH17 cells. Furthermore, TL1A enhances the IL-17 production by committed CD45RO+CCR6+ TH17 cells. TL1A also enhances the induction of RORA mRNA but not RORC mRNA. However, the enhanced RORA mRNA levels corresponded to an increase in IL-17 mRNA under the same conditions suggesting that enhancement of RORA mRNA by TL1A is sufficient to enhance production of IL-17. Our findings establish an important role of TL1A in promoting human TH17 cell differentiation and function and may provide a potential target for therapeutic intervention in TH17 driven diseases.