Lung Microbiome Intervention Attenuates Herpesvirus-Induced Post-HCT Pulmonary Fibrosis Through PD-L1 Upregulation on Dendritic Cells

Abstract

Alterations in the lung microbiome frequently accompany adverse pulmonary outcomes. Hematopoietic cell transplantation (HCT) markedly affects the lung microbiome corresponding with a high incidence of post-HCT pulmonary complications. In a preclinical mouse model of HCT, we observed a reduction in Lactobacillus johnsonii within the lung microbiome following transplantation. Intranasal administration of live or heat-killed (HK) L. johnsonii at low doses reduced gammaherpesvirus-induced pulmonary fibrosis in HCT mice, in which IL-17A plays an essential role. HK L. johnsonii treatment of HCT mice suppressed inflammatory cytokine production by lung macrophages and decreased Il17a expression in T helper 17 (Th17) cells. HK L. johnsonii increased PD-L1 expression on the surface of type II conventional dendritic cells (cDC2) in HCT mice and in vitro in bone marrow-derived dendritic cells (BMDCs). HK L. johnsonii-exposed BMDCs also inhibited IL-17A secretion from co-cultured Th17 cells in a PD-1-dependent manner. Notably, when HK L. johnsonii was administered to HCT mice reconstituted with bone marrow cells from PD-1 knockout (KO) mice, which lack a PD-L1 mediated response, HK L. johnsonii-mediated reduction of pulmonary fibrosis was negated. Collectively, our findings demonstrate that HK L. johnsonii mitigates herpesvirus-induced pulmonary fibrosis in HCT mice by modulating cDC2 surface expression of PD-L1, which subsequently suppresses Il17a expression in Th17 cells, pointing towards a potential postbiotic-based strategy for immunomodulation to address pulmonary complications of HCT.