Opposing Roles of DCs and iNKT Cells in the Induction of Foxp3 Expression by MLN CD25(+)CD4(+) T Cells during IFNγ-Driven Colitis

We have previously shown that a deficiency of CD1d-restricted invariant natural killer T (iNKT) cells exacerbates dextran sulfate sodium (DSS)-induced colitis in Yeti mice that exhibit IFNγ-mediated hyper-inflammation. Although iNKT cell-deficiency resulted in reduced Foxp3 expression by mesenteric lymph node (MLN) CD4(+) T cells in DSS-treated Yeti mice, the cellular mechanisms that regulate Foxp3 expression by CD25(+)CD4(+) T cells during intestinal inflammation remain unclear. We found that Foxp3(−)CD25(+)CD4(+) T cells expressing Th1 and Th17 phenotypic hallmarks preferentially expanded in the MLNs of DSS-treated Yeti/CD1d knockout (KO) mice. Moreover, adoptive transfer of Yeti iNKT cells into iNKT cell-deficient Jα18 KO mice effectively suppressed the expansion of MLN Foxp3(−)CD25(+)CD4(+) T cells during DSS-induced colitis. Interestingly, MLN dendritic cells (DCs) purified from DSS-treated Yeti/CD1d KO mice promoted the differentiation of naive CD4(+) T cells into Foxp3(−)CD25(+)CD4(+) T cells rather than regulatory T (Treg) cells, indicating that MLN DCs might mediate Foxp3(+)CD25(+)CD4(+) T cell expansion in iNKT cell-sufficient Yeti mice. Furthermore, we showed that Foxp3(−)CD25(+)CD4(+) T cells were pathogenic in DSS-treated Yeti/CD1d KO mice. Our result suggests that pro-inflammatory DCs and CD1d-restricted iNKT cells play opposing roles in Foxp3 expression by MLN CD25(+)CD4(+) T cells during IFNγ-mediated intestinal inflammation, with potential therapeutic implications.