Mechanisms of mucosal immunity to oral Shigella infection in a physiological mouse model

Shigella flexneri causes bacillary dysentery, a diarrheal disease responsible for significant global morbidity and mortality. Despite extensive efforts, there is no licensed Shigella vaccine, and due to the lack of tractable and physiological models, mechanisms of adaptive immunity to Shigella are poorly understood. Here, we establish a mouse model that permits mechanistic dissection of adaptive immunity to a physiological oral challenge with Shigella. We find primary Shigella infection confers robust cross-serotype protection against secondary challenge, in a manner strictly dependent on the adaptive immune compartment. Shigella infection induces Shigella-specific CD4+ and CD8+ T cells, but only CD4+ T cells are required for protection. CD4+ T cells produce IFN{gamma} upon secondary challenge, and help B cells produce Shigella-specific IgA. Neither anti-Shigella antibodies nor IFN{gamma} are individually required for immunity to Shigella, but loss of both eliminates protective immunity. Collectively, our results demonstrate that CD4+ T cells orchestrate antibody and cytokine defense against shigellosis.