NFATc3 drives intestinal inflammation by inhibiting regulatory T cells 4149

Abstract Description NFATc3 is a transcription factor essential for T cell activation. It is upregulated in the lamina propria of IBD patients suggesting a role in mucosal inflammation. We investigated the contributions of NFATc3 in colitis and how it affects inflammation controlling regulatory T cells (Tregs). NFATc3 expression was analyzed in IBD patient tissues using qPCR and immunofluorescence. To study its function, NFATc3 knockout (KO) mice were treated with oxazolone to induce colitis. Furthermore, transfer colitis experiments were performed in RAG1 knockout mice to study the effects of NFATc3-deficient T cells. Colonic inflammation was monitored by mini-endoscopy and lamina propria mononuclear cells (LPMCs) were isolated for immunofluorescence. NFATc3 expression was upregulated in tissues from IBD patients. In oxazolone-induced colitis, NFATc3 KO mice showed minimal inflammation, suggesting a role for NFATc3 in promoting colitis. Furthermore, the expression of FoxP3, a marker of Tregs, was significantly increased in NFATc3 KO mice, suggesting that NFATc3 negatively regulates Tregs. Adoptive transfer of NFATc3-deficient T cells into RAG1 knockout mice resulted in delayed onset of inflammation and increased Treg numbers compared to wild-type T cells. NFATc3 promotes intestinal inflammation by suppressing Treg function, which contributes to the development of colitis. Targeting NFATc3 may provide a therapeutic approach to enhance Treg-mediated control of inflammation in IBD. Funding Sources supported by the DFG GE3043/3-1 Topic Categories Mucosal and Regional Immunology (MUC)