Treatment Of Inflammatory Bowel Disease (IBD) By Qa-1-restricted CD8Regulatory T Cells In Mice

Inflammatory bowel diseases (IBD) are severe gastrointestinal disorders including ulcerative colitis (UC) and Crohn's disease (CD). The breakdown of innate immunity and the aberrant activation of the immune system are responsible for tissue damages in IBD patients and animal models. CD4T lymphocytes play an important role in both initiating and regulating intestinal inflammatory immune responses. Until recently, the different types of IBD have been classified as Thl-or Th2-driven diseases for simplification. UC was believed to be a Th2-driven aberrant response while CD is associated with aberrant Thl. In addition, a considerable amount of the studies indicate that Th17cells contribute to IBD in mouse models.Autoimmune diseases, including IBD, occur when the self-reactive immune cells mistakenly attacks the body's own tissues. The immune system, however, has developed multiple self-tolerance mechanisms to spare self tissues or cells from immune attack. Among which, suppression of self-reactive T cells by regulatory cells builds a firm front line in peripheral. A large number of studies have shown that inflammatory bowel diseases are suppressed by CD4+CD25+regulatory T cells in several IBD animal models.Given that lymphocytes with immunosuppressive potential have also been identified in the CD8population, some CD8regulatory T Cells were also be proved to have therapeutic effect on mice IBD mode. In our previous work, we've identified a subset of Qa-1-restricted CD8T Cells responsible for maintain self-tolerance through the inhibiting of auto-reactive CD4T cells and attenuate experimental autoimmune encephalomyelitis (EAE). Because IBD is to a great extent similar to the autoimmune response in multiple sclerosis (MS) and EAE, we were interested in the evaluating the therapeutic effect of Qa-1-restricted CD8T Cells on experimental IBD in mouse and exploring potential therapeutic approaches toward this autoimmune inflammatory disease through the induction of CD8suppressor cells.Qa-1-restricted CD8regulatory cells can be induced by both T cell vaccination and activation of CD4T cells upon peptide immunization. Glatiramer acetate (GA; Copaxone1) is an FDA approved drug for the treatment of multiple sclerosis. Interestingly, previous studies have also demonstrated that GA treatment could ameliorate various pathological manifestations of several IBD animal models. It is generally believe that GA exerts its therapeutic effect on MS through the modulation of CD4Th1-type responses to a protective Th2phenotype. However previous studies have suggested that treatment of multiple sclerosis (MS) with glatiramer acetate (GA; Copaxone1) induces differential up-regulation of HLA-E-restricted CD8cells in human MS patient, which exerts regulatory/suppressor function and is capable of modulating in vivo immune responses by directly killing of CD4pathogenic T cells during therapy.Given that Qa-1(a non-classical MHC class Ib molecule) is the homologous of HLA-E in mice, which is an important molecular in mediating CD8regulatory T cell activity,we then checked whether GA can induce Qa-1-restricted CD8regulatory T cells and tested its therapeutic contributions'in amelioration of the pathological symptoms of experimental IBD in mice.In this study, we showed that CD8T cells from OVA or MOG immunized mice posed therapeutic effect on DSS-induced IBD in mice. GA-induced CD8also showed similar effect in the amelioration of IBD disease manifestations upon adoptive transfer. We further proved that the GA-induced CD8suppressor activity is Qa-1-restricted by using CD8cells from both Qa-1knockout(Qa-1-/-) and mutant knock-in mice (D227K, R72A). Further in vivo tracking experiment demonstrated the preferentially migration of GA-induced CD8cells to inflammatory site. Our work revealed a novel immunologic regulatory role of Qa-1-restricted CD8regulatory T cell in IBD and provided new insights into the immune interplay underlying the disease.