T-bet controls intestinal chronic inflammation via regulation of IL-10 production by CD4 T cells (MUC8P.806)

Abstract The dynamics of pro- and anti-inflammatory cytokine secretion by CD4 T cells is critical for the maintenance of intestinal homeostasis. Disruption of this equilibrium can result in chronic inflammation in the intestine, causing inflammatory bowel disease (IBD). Among the various subsets of CD4 T cells, the Th1 and Th17 subsets are increased in IBD patients and are proposed to be pathogenic. Therefore, understanding the mechanisms by which these cells are regulated is important to expand current treatments of IBD. Using the CD4 T cell dependent adoptive transfer model of colitis, we have investigated the Th1-associated transcription factor, T-bet, in the context of intestinal inflammation. Loss of T-bet results in Th17 skewed immune responses; however, despite wild-type Th17 CD4 T cells being colitogenic, transfer of T-bet deficient naïve CD4 T cells fails to induce colitis in a lymphopenic recipient. Surprisingly, we show that IL-10 production is significantly increased in CD4 T cells in the absence of T-bet. Furthermore, deficiency of both T-bet and IL-10 negates the protective effects of T-bet deficiency alone, as recipients of T-bet-/-IL-10-/- CD4 T cells develop colitis with similar weight loss and histological damage to recipients of wild-type CD4 T cells. Therefore, our data suggests that T-bet plays crucial role in the maintenance of intestinal homeostasis by regulating the intricate balance of effector and regulatory cytokines, in particular IL-10 levels.