Abstract | November 16, 2023

Effective Vaccination for Klebsiella pneumoniae Elicits Epigenetic Changes in T-cells and Requires IL17rc on Lung Fibroblasts

T. Parks Remcho, BS, MD-PhD Candidate, Tulane University School of Medicine, New Orleans, LA

Joseph Hoffmann, PhD, PostDoc, Johns Hopkins University, Baltimore, MD; Naoki Iwanaga, PhD, Nagasaki University Hospital, Nagasaki, Japan; Kejing Song, PhD, Tulane University School of Medicine, New Orleans, LA; Mst. Shamima Khatun, PhD, Tulane University School of Medicine, New Orleans, LA; Jay K. Kolls, MD, PI, Tulane University School of Medicine, New Orleans, LA

Learning Objectives

  1. Describe how some vaccines leverage T cell responses rather than antibody responses.
  2. Explain how vaccine design can be optimized to target multiple pathogens.
  3. Discuss the advantages of mucosal vaccination for respiratory pathogens.

Background
We have previously demonstrated that mucosal vaccination with the Klebsiella pneumoniae outer membrane component OmP-X and the adjuvant LTA-1 elicits antigen-specific lung tissue resident memory T (TRM) cells which afford protection from subsequent Enterobacteriaceae challenge. We have shown that vaccine efficacy requires lung epithelial and fibroblast IL-17RC signaling. However, the downstream effector molecules expressed by these cells remain unclear. Prior studies suggest IL-17RC signaling in fibroblasts regulates several C-C and CXC chemokines that CCL2 (MCP-1) is secreted by fibroblasts in response to IL-17A. Thus, we hypothesized that the CCL2 and its receptor (CCR2) may be required for protective Th17 TRM effector functions.

Methods
Mice with and without a variety of genetic modifications with targeted effects on their lung fibroblasts and circulating monocytes were either vaccinated or treated with a vehicle control. They were subsequently boosted after 21 days. 7-30 days later, they were either challenged with K1 (a hypervirulent Klebsiella pneumoniae strain) or they had their lungs analyzed by flow cytometry using a novel compartment staining modality, by ATAC seq, or using qPCR.

Results
Vaccinated control (C57Bl/6) mice had lower bacterial burdens than their unvaccinated (vehicle control) counterparts. In contrast to control mice, vaccinated mice lacking CCR2 are less protected from challenge. Thus CCR2 is a necessary component of the signaling cascade underpinning vaccine efficacy. Flow cytometry with intravascular staining revealed increased in the macrophage populations in the lung interstitial compartment and showed increased expression of CD206. Further analysis of chromatin condensation by ATAC seq, and mRNA transcript measuring has further elucidated the OmpX LTA1 vaccine’s mechanism of protection.

Conclusions
Fibroblasts require intact IL17rc signaling for TRM mediated vaccine efficacy and may be responsible for effector cell recruitment to the interstitial compartment of the lung in addition to luminal neutrophils. This may prove to be crucial to OmpX LTA1 vaccine efficacy.

References and Resources

  1. Initial Publication on this vaccine from our lab
  2. Naoki Iwanaga et al. ,Vaccine-driven lung TRM cells provide immunity against Klebsiella via fibroblast IL-17R signaling.Sci. Immunol.6,eabf1198(2021).DOI:10.1126/sciimmunol.abf1198
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