P-158 Understanding how GATA3 Expression by Tregs Prevents Pathogenic Tregs

Abstract

Although the etiology of inflammatory bowel disease is still unclear, current evidence suggests that dysregulated immune responses contribute to the disease state. One common approach to current and future therapies is to target mucosal inflammation by interfering with immune pathways. Regulatory T cells (Treg) are known to play a critical role in maintaining homeostasis of the gastrointestinal (GI) tract. While Tregs are critical for maintenance of the GI tract, their dysregulation, either through reduction in number and or function, has been associated with immunopathology. Furthermore, there is mounting evidence that human Treg can aberrantly secrete pro-inflammatory cytokines in settings of autoimmunity. Thus, understanding the factors that stabilize Treg function and survival in highly inflamed settings remains an outstanding question of high clinical relevance. We previously demonstrated that the canonical Th2 transcription factor GATA3 plays an integral role in promoting Treg physiology during inflammation within the gastrointestinal tract, and specifically in regulating inflammation during colitis. GATA3 does this through the dual role of promoting Treg accumulation at the site of inflammation and limiting excessive plasticity of Treg, namely the expression of Th1 (Tbet and IFNg) and Th17 (RORgt and IL-17A) factors. Thus GATA3 plays a multifaceted role in controlling the fate of Treg within inflamed tissues by enhancing both their stability and function. The overall aim of this proposal is to assess the contribution of Treg acquisition of effector function to immunopathology during gastrointestinal inflammation and the mechanism by which GATA3 limits dysregulation of Treg during colitis. Our studies include infection-induced inflammation of the gastrointestinal tract and the CD45RB T cell transfer model of colitis. We now show that Tregs can contribute to disease in infection-induced inflammation. Mice with Tregs that can maintain GATA3 expression have reduced immunopathology. Further, our work reveals a potential role for GATA3 in promoting IL-10 production by Treg during chronic GI infection. Taken together our studies show that Treg dysregulation can cause immunopathology directly. Future studies will examine mechanistically how GATA3 prevents pathogenic Tregs.