Suppressive Macrophages Control the Induction of Transplantation Tolerance.

Abstract

Myeloid derived suppressor cells (MDSC) were initially described as key inhibitors of protective anti-tumor immunity, but emerging evidence suggests that MDSCs are also important mediators of transplant tolerance. Progress in this field has been limited by an inability to discern MDSC from within the greater population of myeloid cells and by a dearth of information regarding mechanisms of MDSC development in vivo. Herein we demonstrate that CD11b+CSF1R+Ly6CloLy6GnegCD169+ MDSC specifically accumulate in allografts of anti-CD154 mAb tolerized transplant recipients, and that these cells prevent CD8+ T cell mediated alloreactivity, promote CD4+Foxp3+ Treg expansion and are required for prolonged allograft survival. The transcriptome analysis of these graft-infiltrating MDSC differs from dendritic cells and corresponds to that of macrophages with inhibitory function. We reveal that CSF1-induced F4/80 expression and cell cycle entry are required for differentiation of these suppressive macrophages from their precursors. Mechanistically, we demonstrate that DC-SIGN (CD209a) controls the immune regulatory function of suppressive macrophages including the ability to induce transplantation tolerance.