Cytotoxic T cells and the epithelium in celiac disease

About This Grant

Project Summary Celiac disease (CD), a disease of small intestinal inflammation, is one of the most common autoimmune diseases with estimated worldwide prevalence >1%. Beyond a lifelong gluten free diet, treatment options for CD are limited. In most cases, the antigen(s) triggering human autoimmune disease is not known, severely hampering our mechanistic understanding of how these diseases are initiated or sustained. The exception is CD. In CD, the triggering antigen is dietary gluten, which activates gluten-specific CD4+ T cells. Not only is the antigen trigger in CD known, but its exposure can be controlled, providing truly unique opportunities to study human autoimmunity. The critical question of how a CD4+ T cell response directed against dietary gluten culminates in self-tissue damage by cytotoxic CD8+ αβ and γδ T cells, which are not thought to recognize gluten themselves, remains unanswered. The current model for celiac pathogenesis posits that cytotoxic CD8+ αβ and γδ T cell activation occurs downstream of CD4+ T cell-driven inflammation. Our preliminary data inform a revised model for CD pathogenesis, which will be applicable in autoimmune diseases beyond CD. Our central hypothesis to explain CD-mediated tissue destruction is that gluten-specific CD4+ T cells and cytotoxic T-IELs activate in parallel following gluten ingestion, with the latter cell population requiring additional tissue-derived signals for full activation. A critical aspect of our model is that CD4+ and CD8+ and γδ T-IELs have different antigen specificities. To investigate these hypotheses and dissect mechanisms through which an aberrant CD4+ T cell response to gluten culminates in specific tissue damage by cytotoxic T-IELs, we propose the following Aims. Aim 1. Dissect mechanisms through which gluten modulates Natural T-IEL populations in CD. Aim 2. Dissect the role of tissue- derived factors in unleashing the cytotoxic capacity of T-IELs in CD. Successful completion of these aims will advance our mechanistic understanding of CD and autoimmunity, and could inform novel therapeutic strategies.