CD200+ fibroblasts prime the immunoregulatory function of granulocytic myeloid-derived suppressor cells in inflammatory arthritis

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Abstract
Granulocytic myeloid-derived suppressor cells (G-MDSCs) are immunoregulatory cells of the neutrophil lineage. Here, we show that immunoregulation by G-MDSCs is imprinted by the joint tissue microenvironment in patients with axial spondyloarthritis and in animal models of inflammatory arthritis. We demonstrate that the suppressive function of G-MDSCs is significantly enhanced in the joint tissue, but not in the circulation. Analysis of public single-cell RNA sequencing datasets was consistent with Cd200r1 high Hmgb2 + precursors differentiating into G-MDSCs following interaction with Cd200 + fibroblasts. In hTNFtg/ Il23mc mice, treatment with a CD200R1 agonist promoted an immunoregulatory signature associated with PD-L1 expression, whereas CD200 blockade reversed the phenotype. Following adoptive transfer of G-MDSC precursor cells into arthritic mice, administration of a CD200-blocking antibody impaired the differentiation of PD-L1 + G-MDSCs and exacerbated disease severity. These findings reveal a tissue-intrinsic program that facilitates resolution of inflammation through fibroblast-myeloid crosstalk that enhances G-MDSC function.

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