Citrobacter rodentium induces tissue-resident memory CD4 + T-cells.

Tissue resident memory (TRM ) T-cells are a novel population of tissue restricted antigen specific T-cells. TRM are induced by pathogens and promote host-defense to secondary infections. Although TRM cells cannot be detected in circulation, they are the major memory CD4+ and CD8+ T-cell population in tissues in mice and humans. Murine models of CD8+ TRM cells have shown that CD8+ TRM cells maintain tissue residency via CD69 and though tumor growth factor β dependent induction of CD103. In contrast to CD8+ TRM cells, there are few models of CD4+ TRM cells. Thus, much less is known about the factors regulating the induction, maintenance and host-defense functions of CD4+ TRM cells. Citrobacter rodentium is known to induce IL-17+ and IL-22+ CD4+ T-cells ('Th 17' and 'Th 22' cells, respectively). Moreover, data from IL-22 reporter mice shows that most IL-22+ cells in the colon 3 months post- C. rodentium are CD4+ T-cells. This, collectively suggests that C. rodentium may induce CD4+ TRM cells. Herein, we demonstrated that C. rodentium induces a population of IL-17A+ CD4+ T cells that are tissue restricted and antigen specific thus meeting the criteria of CD4+ TRM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naïve and effector T-cells but not tissue restricted T-cells, we show that these CD4+ TRM cells can promote host defense.