Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection

Mucosal antigen-specific CD4 T cell responses to intestinal pathogens remain incompletely understood. Here we examined the CD4 T cell response after oral infection with an internalin A ‘murinized’ Listeria monocytogenes (Lm). Oral Lm infection induced a robust endogenous listeriolysin O (LLO)-specific CD4 T cell response with distinct phenotypic and functional characteristics in the intestine. Circulating LLO-specific CD4 T cells transiently expressed the ‘gut-homing’ integrin α(4)β(7) and accumulated in the intestinal lamina propria and epithelium where they were maintained independent of IL-15. The majority of intestinal LLO-specific CD4 T cells were CD27(−) Ly6C(−) and CD69(+) CD103(−) while the lymphoid LLO-specific CD4 T cells were heterogeneous based on CD27 and Ly6C expression and predominately CD69(−). LLO-specific effector CD4 T cells transitioned into a long-lived memory population that phenotypically resembled their parent effectors and displayed hallmarks of residency. In addition, intestinal effector and memory CD4 T cells showed a predominant polyfunctional Th1 profile producing IFNγ, TNFα and IL-2 at high levels with minimal but detectable levels of IL-17A. Depletion of CD4 T cells in immunized mice led to elevated bacterial burden after challenge infection highlighting a critical role for memory CD4 T cells in controlling intestinal intracellular pathogens.