Lung Th17 cells signal via fibroblasts, establish interstitial macrophages, and contribute to host protection

Pneumonia is the leading killer of children globally and a significant cause of morbidity and mortality in the US. Pneumonias due to drug-resistant Enterobacteriaceae are an emerging problem. Our lab has shown that lung tissue resident memory (TRM) cells, consisting of Th17 and Th1 cells, provide profound protection against hyper-virulent K. pneumoniae strains. Interestingly, these cells must signal through lung fibroblasts to provide protection as deletion of IL-17RC in Dermo1+ or Col1a2+ cells compromises TRM efficacy. Based on our prior work and preliminary results, we hypothesize that vaccine-induced Th17 cells signal lung fibroblasts to secrete the chemokines responsible for recruiting macrophages to the interstitial compartment of the lung and improve the ability of local macrophages to clear K. pneumoniae. To test this, we propose the following aims: Aim 1: Evaluate the response of lung fibroblasts to Th17- associated cytokines (IL17A, IL17F, TNF) and examine the chemotactic and phenotypic impact fibroblast-derived signals have on several myeloid/monocyte populations. Aim 2: Evaluate the dependence of bacterial clearance on vaccine-elicited host TRM populations, fibroblast signaling, and myeloid cell recruitment and modification in vivo. We propose the macrophage population recruited via fibroblast signaling is (a) the direct downstream result of establishing TRM cells, (b) key to vaccine efficacy, and (c) phenotypically and locationally well-suited to clearance of the pathogen.