Understanding the contributions of MAIT cells in colitis - PROJECT SUMMARY Despite existing immunosuppressive and anti-inflammatory treatments for IBD, the disease remains lifelong, and a burden for healthcare systems. Current treatments have variable efficacy, potential for sudden failure, and severe side effects. Novel immune targets are needed for developing universally effective therapies for managing active disease, regardless of genetic background. Additionally, relevant mouse models mimicking human IBD are essential to understand how these immune cells drive inflammation in patients. Mucosal-Associated Invariant T (MAIT) cells have gained significant attention due to their evolutionary conservation, abundance in humans, ability to recognize a range of microbes, and their roles in various diseases. They are highly enriched in mucosal and peripheral tissues, such as the gastrointestinal tract. MAIT cells express a T cell receptor (TCR) that recognizes microbial metabolites presented by MR1, a non-classical MHC molecule. At steady-state, MAIT cells express high levels of tissue homing molecules, and upon activation, MAIT cells produce inflammatory cytokines. These functional features of MAIT cells position them as key therapeutically relevant players in the modulation of inflammation at barrier tissues. However, in most standard laboratory strains of mice, the numbers of MAIT cells are extremely low, making in vivo studies challenging. The CC strain, CC011/Unc were previously shown to develop spontaneous non-lethal colitis with age. The establishment of this strain at our animal facility recapitulates features of chronic colitis including, colon thickening and ulceration, prominent lymphocytic and PMN infiltration of the mucosa and muscularis layer. Strikingly, we demonstrate that CC011 exhibits a high number of MAIT cells at steady state, moreover, the number of MAIT cells in the colon significantly increases during the development of colitis. Like human IBD, severe intestinal barrier disruption occurs, along with an influx of neutrophils, macrophages, TH17 cells, and inflammatory mediators such as IL-1α, IL-1β, and IFN-γ. Crucially, genetic deletion of the T cell receptor gene, Traj33 in CC011 resulted in almost obliterated MAIT cell development, and this coincides with a dramatic reduction in colon tissue injury and inflammation. We hypothesize that MAIT cells are intrinsically pathogenic and key to the development and maintenance of colitis. To test this hypothesis using single cell transcriptomics and leveraging our unique access to IBD patient samples, we will determine whether MAIT cells have pathogenic traits in human IBD (Aim 1). We will address the therapeutic potential of MAIT cells by modulating MAIT cells in vivo with potent MAIT TCR agonists and pro- inflammatory cytokines in the translationally relevant CC011 experimental model of spontaneous colitis (Aim 2). This proposal will provide new insights into the inflammatory networks that drive disease progression, pinpointing the mechanisms that drive MAIT cell pathogenicity during colitis and establish their role in instigating and maintaining disease. This work will also help determine the potential of MAIT cells as new therapeutic targets for treating active disease.
