Citrobacter rodentium Induces Tissue-Resident Memory CD4⁺ T Cells

Tissue-resident memory T cells (T_RM cells) are a novel population of tissue-restricted antigen-specific T cells. T_RM cells are induced by pathogens and promote host defense against secondary infections. Although T_RM 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⁺ T_RM cells have shown that CD8⁺ T_RM cells maintain tissue residency via CD69 and though tumor growth factor β-dependent induction of CD103. In contrast to CD8⁺ T_RM cells, there are few models of CD4⁺ T_RM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4⁺ T_RM cells. Citrobacter rodentium is known to induce IL-17⁺ and IL-22⁺ CD4⁺ T cells (T_h17 and T_h22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22⁺ cells in the colon 3 months after C. rodentium infection are CD4⁺ T cells. This collectively suggests that C. rodentium may induce CD4⁺ T_RM cells. Here, we demonstrate 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⁺ T_RM 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 naive and effector T cells but not tissue-restricted T cells, we show that these CD4⁺ T_RM cells can promote host defense.