Characterization of bronchovascular-bundle mesenchymal stromal cells regulating antibody-secreting cell niche in rejecting lung allografts

A transplanted lung offers a permissive milieu for local adaptive immune cell responses. Here, we characterize a transcriptionally and anatomically distinct adult lung-resident mesenchymal stromal population (MSC) that supports a pro-survival niche for antibody-secreting cells in rejecting lung allografts through a novel IL-6 trans-signaling/CXCL12 axis. By using a mouse orthotopic lung transplant model and Blimp1YFP recipients, we identify spatial localization of antibody-secreting cells (ASCs) and terminally differentiated plasma cells (PCs) along the bronchovascular bundles (BVBs). A previously described Foxf1+/Gli1+/Itga8-subset of collagen-expressing MSCs, which forms a 3-dimensional network along the bronchovascular bundles (BVB-MSCs), was found to be the major source of the PC survival factors CXCL12 and IL6. Cxcl12iCre/ERT2R26RtdTomato mice utilized as donors validated the expansion of this population in a rejecting graft and their intimate association with ASCs. CXCL12 expression was increased in allografts and Foxf1+ MSCs isolated from human CLAD patients. IL6 trans signaling/STAT3 signaling axis was shown to upregulate CXCL12 secretion in human MSCs, and Olamkicept-mediated neutralization of IL6 trans-signaling in murine RAS attenuates CXCL12 expression, intra-graft ASC population, and fibrogenesis. Our findings represent the first delineation of specialized CXCL12-expressing stromal cells in adult lungs and demonstrate their contribution to sustaining intragraft ASC niches and allograft fibrogenesis.