Regulation Of Thl7Cell Differentiation By Monocytic Myeloid-Derived Suppressor Cells Through Membrane-bound TGF-β1in Collagen Induced Arthritis

Myeloid-derived suppressor cells (MDSCs), a heterogeneous population ofimmature myeloid cells, has the ability to suppress T cell proliferation. Although ithas received substantial attention, the definite role of MDSCs and two subsets(Monocytic myeloid-derived suppressor cells and Granuocyticmyeloid-derivedsuppressor cells, M-MDSCs subset and G-MDSCs subset) in promotion ofrheumatoid arthritis (RA) remain elusive. In the present study, we investigated thefrequency changes of MDSCs and two subsets as well as the relationship betweenMDSCs and Th17cell differentiation in collagen induced arthritis (CIA) mice, awell-characterized experimental model of human RA. We observed that M-MDSCssubset abundantly accumulate in the spleen of CIA mice, suggested the important roleof M-MDSCs in CIA development. Compared with the depletion of G-MDSCs byLy6G monoclonal antibody (mAb), elimination of M-MDSCs subset in vivo markedlydecreased severity of clinical symptoms accompanied with less pronounced synoviumhyperplasia and joint damage and delayed disease onset through inhibition ofpathogenic Th17immune responses. Further studies showed that only co-culture ofM-MDSCs subset with CD4+CD62L+naive T cells can induce the differentiation ofCD4+CD62L+naive T cells into Th17subset, as indicated by significantly increasednumber of Th17cells, elevation of IL-17A production, and up-regulation RORγttranscript. Moreover, membrane-bound TGF-β1expressed on M-MDSCs subsetinvolved in cell-cell contact between M-MDSCs subset and CD4+CD62L+naive Tcells has been demonstrated to be essential for Th17cell differentiation and CIApathogenesis. These results provide a deep understanding of the immunoregulatorymechanisms of MDSCs and two subsets in CIA pathogenesis and may help usdevelop potential therapeutic regimens against RA.