A NEWLY DISCOVERED REGULATORY CD8 T CELL NETWORK HAS THE POTENTIAL TO REGULATE AND ELIMINATE PATHOGENIC CD4 T CELLS IN AUTOIMMUNE MEDIATED DISEASE OF THE GUT

Abstract

Abstract INTRODUCTION Several groups have described a subset of CD8 T cells with immunosuppressive characteristics in inflammatory disease settings. The increased prevalence of a defined subset of CD8 T cells and correlation to disease has been reported in mouse and human autoimmune diseases, suggesting a protective role for select CD8 T cells in autoimmunity. We hypothesized that a dysregulated regulatory CD8 T cell (CD8 Treg) network was similarly involved in the pathology of autoimmune diseases of the gut, including Celiac disease, Crohn’s, and Ulcerative Colitis. Recently, investigators have described CD8 Treg activation through a canonical T cell receptor that results in oligoclonal expansion and perforin dependent elimination of pathogenic CD4 T cells in animal models. Here, we have demonstrated the presence of this CD8 Treg cell network in Celiac patients and its potential to regulate and eliminate pathogenic CD4 T cells. METHODS Using antigen induced animal models of autoimmunity, as well as PBMCs and tissues derived from patients with Celiac disease, we have developed assays to evaluate CD8 Tregs. Our approach integrates imaging, gene expression, flow cytometry, and quantification of soluble analytes following gluten exposure. This platform may be extended to evaluate the CD8 Treg network following exposure to an antigenic trigger resulting in disease flare, including in diseases with poorly defined antigenic triggers, such as Crohn’s and colitis. RESULTS We have characterized a surface and functional phenotype associated with CD8 Treg prevalence and activation via agonism of a native TCR. Using this phenotype, we then confirmed the presence and prevalence in Celiac patient PBMCs and duodenal tissues and distinct from CD8 T cells (Figure 1). Activation resulted in a rapid and specific cytolytic mechanism of action in mouse and human CD8 Treg cells. CD8 Treg in Celiac patients are not inherently dysfunctional, as activation of celiac patient CD8 Tregs resulted in the elimination of pathogenic CD4 T cells, which are responsible for the initiation and perpetuation of tissue destructive inflammation in Celiac disease and IBD. Using Celiac disease as platform to introduce a known antigenic trigger for autoimmunity, we have established a panel of phenotypic and functional markers to define CD8 Tregs and their activity in patients with other autoimmune diseases, including Crohn’s disease and Ulcerative Colitis. CONCLUSION We postulate the importance of a newly described regulatory network in autoimmune mediated gut disorders and other inflammatory disease. This network can potentially be targeted by immune-modulating biologics, to suppress pathogenic T cells, reduce disease severity & onset, as well as mitigate flare severity & frequency.