Dietary Antigens Drive Protective Innate-like CD4 T Cell Immunity at the Mucosal Barrier of the Small Intestine

CD4 T helper (Th) cells reprogram to cytotoxic T lymphocytes (CTLs) in the intestinal epithelium during steady state. The unique localization of mucosal CD4 CTLs, in the absence of a pathogenic threat, suggests local non-pathogen antigens and organ-specific properties direct the CTL conversion. Similar to myeloid antigen presenting cells, intestinal epithelial cells (IECs) constitutively express MHC class II (MHCII), indicating crosstalk with nearby CD4 T cells. IECs constantly absorb and process luminal digested proteins and present these dietary antigens to neighboring CD4 T cells on their basolateral side. We have generated solid evidence with murine conditional knock-out and bone marrow chimera models that MHCII+ IECs and the dietary epitopes they present are instrumental in the development of small intestinal CD4 CTLs in a homeostatic, non-inflammatory environment. These dietary antigen-specific CD4 CTLs accumulate over time as innate-like protective cells that fortify the epithelium with a pre-existing protective arm. As fully differentiated and functional resident T cells, CD4 CTLs are aptly designed to rapidly respond, independent of pathogen specificity, and contain infections. Using Salmonella as an enteric pathogen model, the data show that dietary antigen-specific CD4 CTLs have the capacity to rapidly and effectively kill infected epithelial cells, thereby preserving the integrity of the barrier and blocking systemic spreading of the pathogen. The double-pronged ability for CD4 CTLs to protect against invaders while also mitigating immunopathology, by differentiating inflammatory CD4 T cells into excellently trained CD4 CTLs, reveal previously unknown mechanisms of mucosal lymphocyte biology.