IL-6 trans-signaling regulates CXCL12 expression in mesenchymal stromal cells and plasma cell niche in rejecting lung allografts.

UNLABELLED: 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 Blimp1 EYFP 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 IL-6. Cxcl12 iCre/ERT2 Rosa26 tdTomato 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 murine allografts and in Foxf1 + mesenchymal cells (MCs) isolated from human CLAD patients. IL-6 trans-signaling/STAT3 signaling axis was shown to upregulate CXCL12 secretion in human MCs, and Olamkicept-mediated neutralization of IL-6 trans-signaling in murine RAS attenuates CXCL12 expression, intra-graft ASC population, and fibrogenesis. Our findings represent the first delineation of specialized CXCL12-expressing mesenchymal stromal cells in adult lungs and the contribution of IL-6 trans-signaling driven CXCL12 expression to sustaining intra-graft ASC niches and allograft fibrogenesis.

ONE SENTENCE SUMMARY: We characterize CXCL12-expressing mesenchymal cells and their role in a pro-survival niche for antibody-secreting cells in rejecting lung allografts.