UC San Diego

During steady state, 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 may represent a strategy of avoiding CD4 Th-mediated inflammation. Using both an in vitro differentiation model as well as transgenic models, where CD4 T cell fates are forced into predetermined phenotypes, the conversion of Th to CTL was found to mitigate disease pathology and promote tolerogenic conditions. After defining the role of CD4 T cells during steady state, we then assessed the ability of CD4 CTLs to respond to enteric pathogens. Pre-existing CD4 CTLs were found to have the capacity to kill Salmonella enterica-infected cells, thereby preserving the integrity of the barrier and preventing bacterial dissemination. Furthermore, we identified IL-15/IL-15Ra complex trans-presentation as a mechanism of inciting CD4 CTLs to become active killers. Functionally, CD4 CTLs represent a strategy of the immune system to fortify the epithelium with quiescent but primed CTLs that can provide rapid immunity during enteric infection. The generation of CD4 CTLs during steady state and their functional relevance during infection is a novel strategy of mucosal immunity that can be defined as ‘protective tolerance’.