Role of E3 ubiquitin ligase GRAIL in B cell activation and tolerance

Abstract

Abstract To date, B cells are believed to play a central role in pathogenesis of various autoimmune diseases as loss of B-cell tolerance with emergence of autoreactive B cells and pathogenic autoantibodies are the hallmark features of autoimmune disorders; however the intrinsic mechanisms that underlie initial breaks in B cell tolerance have not been completely defined. GRAIL, gene related to anergy in lymphocytes (encoded by Rnf128) is an E3 ubiquitin ligase associated with CD4+ and CD8+ T cell tolerance. Our data for first time show GRAIL expression in both mouse and human B cells, with higher expression in anergic B cells and that GRAIL deficiency in B cells leads to impaired B cell peripheral tolerance induction and greater susceptibility to autoimmune diseases. GRAIL deficient B cells exhibited hyperresponsivness in terms of proliferation and antibody production upon antigen stimulation in vitro and in vivo. Concomitantly, GRAIL-deficient B cells were less efficient in downregulation of IgM after B cell receptor (BCR) crosslinking and exhibited increased CD79a expression and activation leading to elevated activation of proximal BCR-signaling components and Ca2+mobilization; GRAIL expression promoted CD79a ubiquitination and degradation. Interestingly, GRAIL expression is also essential to control antigen-presenting property of B cells towards T helper 1 (Th1), Th2, Th17 and follicular helper T (Tfh) cells; since GRAIL deficiency in B cells leads to augmented development and function of Th1, Th2, Th17 and Tfh cells in vitro and in vivo. Thus, our results indicate that GRAIL is a crucial intrinsic factor controlling B cell activation and tolerance by targeting of BCR component CD79a for degradation.