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

Abstract

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.

Germline IgM predicts T cell immunity to Pneumocystis

“…To determine if these antigen enriched CD4+ T cells had effector activity, we immunized mice with Meu10 (Figure 5A) or PNEG_01454 with the strong mucosal adjuvant LTA1 which induces robust antigen specific Th1/Th17 responses (15). Vaccine elicited cells were harvested from the lung and adoptively transferred into recipient Rag2-/-mice to allow homeostatic proliferation for two weeks followed by PC inoculation, as previously described (6).…”

“…To generate Pneumocystis antigen specific CD4+ T cells, female C57BL/6 mice were intratracheally immunized with 10μg Meu10 plus 10μg LTA1, 10μg PNEG_01454 plus 10μg LTA1 or 10μg LTA1 only, and boosted once 3 weeks later. We chose LTA1 as it induces strong lung Th1 and Th17 cells (15). One week after boosting, the lungs were harvested and single cell suspensions prepared.…”

Advancing Lung Immunology Research: An Official American Thoracic Society Workshop Report

“…In the context of chronic inflammation, adventitial domains give rise to tertiary lymphoid structures, such as inducible bronchus-associated lymphoid tissue (iBALT) ( 150 ). Certain types of CD4 + Trm cells have been shown to persist in iBALT ( 115 , 157 , 158 ). In addition, although organ transplant studies reveal that Trm cells can persist for years, studies in mice and humans have suggested that Trm cells may be capable of egress from peripheral tissues, presumably via adventitial lymphatics, and join the circulating memory T cell compartment, while maintaining features of the Trm program and exhibiting a predilection to return to the tissue of origin ( 159 – 162 ).…”

Innovative vaccine approaches—a Keystone Symposia report

“…Finally, since OMPX is highly conserved, the vaccine has the potential to protect across Enterobacteriaceae species. In in vitro assays, the vaccine induced an immune response against an array of Enterobacteriaceae species, while it demonstrated protection against S. marcescens in vivo 125 …”

“…In in vitro assays, the vaccine induced an immune response against an array of Enterobacteriaceae species, while it demonstrated protection against S. marcescens in vivo. 125…”