Altered response of CD4+ T cells to TGF-β and IL-6 in the absence of the vitamin D receptor (88.9)

Abstract

Abstract Th17 cells play critical roles in autoimmunity. The active form of vitamin D, 1,25(OH)2D3, has been shown to directly regulate T cell function, but the role of vitamin D and vitamin D receptor (VDR) in the differentiation of Th17 cells is not very clear. Induction of Th17 cells using TGF-β and IL-6 resulted in twice as many Th17 cells in VDR KO cultures as WT. The increased frequency of Th17 cells in VDRKO cultures was not a result of higher expression of retinoic acid receptor-related orphan receptor-γT (ROR-γT). 1,25(OH)2D3 deficient CD4+ T cells also overproduced IL-17. Treatment of WT CD4+ T cells with 1,25(OH)2D3 significantly inhibited the generation of Th17 cells. The number of Treg cells in Th0 cultures of CD4+ cells from VDR KO mice was higher, compared to WT. TGF-β addition to the cultures induced Tregs in both the VDR KO and WT cultures, but there were significantly more Tregs in WT than VDR KO cultures. Addition of both TGF-β and IL-6 to WT CD4 cultures caused a 4-fold reduction in Treg cells. The reduction of Tregs by TGF-β and IL-6 in VDR KO cultures was only 2-fold. VDR KO T cells cultured with TGF-β and IL-6 produced significantly more IL-10 than their WT counterparts. Our data suggest the 1,25(OH)2D3 and signaling through the VDR are important regulators of Th17 differentiation. Furthermore, VDR KO T cells have altered responses to TGF-β and IL-6 that resulted in increased numbers of both Th17 and Treg cells.