During the 2-year project period, we adopted a stepwise approach to investigate the activation, function and migration of T lymphocytes specific for commensal microbes that are relevant to human IBD. First, we set up an in vivo model for the study of T cell activation against commensal bacteria in the context of intestinal inflammation. By injecting commensal-specific lymphocytes into mice undergoing colitis and monitoring accumulation of those cells in different lymphoid organs, we identified the preferential location where the commensal-specific immune response is initiated during colitis. Next, we used different state-of-the-art experimental approaches to analyse the function of commensal-specific lymphocytes during acute and chronic colitis. Hence, we generated needed evidence for the pro-inflammatory potential of commensal-specific cells. Moreover, we observed the ability of activated commensal-specific lymphocytes to migrate to the colon mucosa in two separate models of colitis, suggesting this selective migration as a possible target for intervention in colonic IBD. Further experiments are currently investigating the molecular requirements for such migration.
Together with their migratory potential, we also demonstrated the capacity of commensal-specific cells to reshape their function over time and in different anatomical locations. We believe that this is another important node for therapeutic intervention, as we show for the first time that the commensal-specific immune response can be reshaped under specific conditions. Dissemination of this observation via project meetings and international retreats has rapidly given rise to new collaborative projects aimed at identifying strategies to actively reshape the commensal-specific immune response and restore intestinal homeostasis.
