Masato Tsuda 1 , 4 , Hussein Hamade 1 , Lisa S. Thomas 1 , Brenda C. Salumbides 1 , Alka A. Potdar 1 , Michelle H. Wong 1 , Jordan S. Nunnelee 1 , Jasmine T. Stamps 1 , Anita Vibsig Neutzsky-Wulff 1 , Robert J. Barrett 1 , 2 , Yizhou Wang 3 , Jie Tang 3 , Vincent A. Funari 3 , Stephan R. Targan 1 , Kathrin S. Michelsen 1 , *
07 January 2019
T helper 9 (T H9) cells are important for the development of inflammatory and allergic diseases. The T H9 transcriptional network converge signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as strong inducer of mouse and human T H9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under T H9 and T H9-TL1A polarizing conditions. In vivo, using a T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, T H9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3 −/− T H9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes T H9 cell differentiation and function and define a role of BATF3 in T cell driven mucosal inflammation.