Vaccine-driven lung TRM cells provide immunity against Klebsiella via fibroblast IL-17R signaling.

Tissue-resident memory (TRM) cells are thought to play a role in lung mucosal immunity to pathogens, but strategies to elicit TRM by mucosal vaccines have not yet been fully realized. Here, we formulated a vaccine composed of outer membrane protein (Omp) X from Klebsiella pneumoniae and LTA1 adjuvant that was administered by the intrapulmonary route. This vaccine elicited both T _H 1 and T _H 17 cells that shared transcriptional features with cells elicited by heat-killed K. pneumoniae . Antibody responses were required to prevent bacterial dissemination but dispensable for lung-specific immunity. In contrast, lung immunity required CD4 ⁺ T cells, STAT3 expression, and IL-17R signaling in fibroblasts. Lung-specific CD4 ⁺ T cells from OmpX+LTA1–immunized mice were observed homing to the lung and could mediate protection against infection in an adoptive transfer model. Vaccine-elicited T _H 17 cells showed reduced plasticity and were resistant to the immunosuppressant FK506 compared with T _H 1 cells, and T _H 17 cells conferred protection under conditions of transplant immunosuppression. These data demonstrate a promising vaccine strategy that elicits lung TRM cells and promotes serotype-independent immunity to K. pneumoniae.