GRAIL controls intestinal inflammation by regulating IL-10 receptor expression in T cells 9403

Abstract Description Intestinal homeostasis depends on interaction between the microbiota and host immune system, and disruption of this balance results in predominance of inflammatory responses leading to inflammatory bowel disease. However, to date, precise cell-intrinsic regulatory mechanisms that controls intestinal inflammation are poorly understood. Here we show that expression of the E3 ubiquitin ligase, gene related to anergy in lymphocytes (GRAIL) is diminished in colon tissues of patients and mice with colitis and GRAIL deficiency leads to increased susceptibility to colitis. Importantly, GRAIL deficiency in hematopoietic cells, particularly in CD4+ T cells disrupted pro-/anti-inflammatory balance towards inflammatory immune responses at the steady state and during colitis. Mechanistically, loss of GRAIL intrinsically diminished the expression of interleukin (IL)-10 and IL-10 receptor (IL-10R) specifically in CD4+ T cells in colonic mucosa. Moreover, GRAIL orchestrates IL-10R expression in T cells through transcriptional and post-translational ubiquitin-dependent regulation. Besides the intestinal immunity, GRAIL deficiency in T cells leads to a decrease in microbial diversity and an enrichment of pro-inflammatory microbiota. Colonization of wild-type mice with microbiota from GRAIL deficient mice is associated with severe colitis. Thus, GRAIL plays a protective role during intestinal inflammation by supporting regulatory immune responses and shaping the microbiota. Funding Sources This work was supported by NIH R01 and R03 grants (R.N.), and Institutional Research Grant (IRG) (R.N.). Topic Categories Mucosal and Regional Immunology (MUC)