Parenteral vaccination protects against mucosal Salmonella infection by inducing liver tissue resident memory CD4 T cells.

Salmonella enterica is a gastrointestinal pathogen that causes a variety of intestinal and systemic clinical disease. Vaccine development for systemic salmonellosis requires a deeper understanding of protective mechanisms and the relative contribution of mucosal and systemic host responses to bacterial elimination. Here, we examined the relative importance of mucosal and systemic immunity in the control of systemic salmonellosis. Delivery of a live-attenuated vaccine strain via a parenteral route did not elicit a substantial mucosal immune response, but was still sufficient to protect mice from systemic Salmonella infection. A prominent feature of the protective systemic response was the establishment of Salmonella-specific tissue resident memory (TRM) CD4 T cells in the liver. Although adoptive transfer of hepatic TRMs was sufficient to protect mice from challenge infection, TRMs from the intestinal lamina propria reduced bacterial loads but failed to fully protect mice from infection. The protective contribution of liver and LP TRMs was partially dependent on the expression of IL-18R and the corresponding ability to elicit noncognate CD4 T cell responses in vivo. Overall, these data suggest that a parenteral vaccination approach that efficiently induces liver TRMs expressing IL-18R should provide robust protection against mucosal or systemic infection with Salmonella.