Small Intestine Epithelial CD4 Cytotoxic T Lymphocytes Provide Innate-Like Protection against Enteric Pathogens without Risk of Immunopathology

Abstract

Abstract CD4 T helper (Th) cells reprogram to cytotoxic T lymphocytes (CTLs) in the small intestinal epithelium. In the present study, CD4 CTLs were evaluated for their potential to promote tolerance during steady state as well as their ability to fend off enteric pathogens during infection. The CD4 T cell adoptive transfer model of colitis was used to determine if CTLs can promote tolerance. Naïve CD4 T cells were differentiated towards a CTL, Treg, or inflammatory Th (Th1 or Th17) fate and transferred into RagKO recipients. Strikingly, the recipients that received CTLs, like the Treg condition, had minimal disease; in contrast, the Th conditions all exhibited pathology. To determine if the forced presence of Th cells exacerbates colitis disease, CD4 T cell adoptive transfers were performed using cells that were forced to stay Th or predisposed to becoming CTLs. Altogether, the conversion of Th to CTL mitigated disease pathology and promoted tolerogenic conditions. The protective role of CD4 CTLs to rapidly respond to enteric pathogens and contain infections was also examined. Using Salmonella as a bacterial model, the data show that pre-existing CD4 CTLs have the capacity to kill infected cells, thereby preserving the integrity of the barrier and preventing bacterial dissemination. Functionally, CD4 CTLs represent a strategy of protective tolerance by the immune system to fortify the epithelium with quiescent but primed CTLs that can provide rapid immunity during enteric infection. Supported by grants from the NIH (U01 AI125957, F31 DK124078)