Targeted lung Lactobacillus johnsonii intervention alleviates virus-induced fibrosis post-HCT through PD-L1/PD-1 signaling

Our study highlights the decrease of Lactobacillus johnsonii in the lungs following hematopoietic cell transplantation (HCT) and its immunomodulatory effects in attenuating post-HCT pulmonary complications. Introducing live or heat-killed L. johnsonii into the lungs of HCT mice significantly reduced gammaherpesvirus-induced lung inflammation and fibrosis. This protective effect was mediated in part by the up-regulation of PD-L1 on dendritic cells, which in turn dampened the production of the inflammatory cytokine IL-17A by T helper 17 cells post-HCT. L. johnsonii also reduced Tgfb1 expression in lung macrophages. These anti-fibrotic effects of heat-killed L. johnsonii were absent in PD-1-deficient mice, highlighting the role of PD-L1/PD-1 signaling. Further analysis showed that dendritic cells uniquely recognized L. johnsonii and increased PD-L1 expression via TLR1/2- and TLR9-MyD88 pathways. Our findings suggest that heat-killed lactobacilli could serve as a safe postbiotic therapy to moderate immune responses and reduce lung inflammation and fibrosis post-HCT, offering a strategy for managing transplant-related lung complications.