DC-SIGN+ Macrophages Control the Induction of Transplantation Tolerance

Abstract

SUMMARY Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8+ T cell immunity and promoted CD4+Foxp3+ Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN+ suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

“…This similarity emerged when we used subsets of most variable genes across tissue MFs, tissue DCs, M-MDSCs and Tip-DCs ( Figure S3A), as well as a set of previously described gene signatures specific for DCs , macrophages and M-MDSCs ( Figure S3B) (Conde et al, 2015).…”

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

“…These inflammatory macrophages are characterized phenotypically by their high expression of Ly6C (Ly6C hi or M1) (4). Recent evidence suggests that macrophages are also important during the induction of transplantation tolerance (5). Presence of graft infiltrating macrophages has been described in long-term surviving transplant recipients and these immunosuppressive macrophages are associated with unresponsiveness to the transplanted organ (6).…”

“…Presence of graft infiltrating macrophages has been described in long-term surviving transplant recipients and these immunosuppressive macrophages are associated with unresponsiveness to the transplanted organ (6). These suppressive macrophages are characterized phenotypically by their low expression of Ly6C (Ly6C lo or M2) (5). This suggests that graft-infiltrating monocytes differentiate into either immunogenic (Ly6C hi ) or tolerogenic (Ly6C lo ) macrophages, which determines the outcome of the immunological response.…”

“…This suggests that graft-infiltrating monocytes differentiate into either immunogenic (Ly6C hi ) or tolerogenic (Ly6C lo ) macrophages, which determines the outcome of the immunological response. While the phenotype and function of macrophages that mediate the induction of transplantation tolerance has recently been reported (5), their developmental requirements remains poorly understood.…”

“…Inflammatory Ly6C hi monocytes are rapidly recruited to inflamed tissues and become alternatively activated Ly6C lo macrophages once the inciting inflammatory stimulus has been resolved (9). In organ transplantation, inflammatory Ly6C hi monocytes infiltrate the allograft early after transplantation and differentiate into suppressive Ly6C lo macrophages following costimulatory blockade (5). Therefore, the signals that dictate macrophage polarization towards alternatively activated Ly6C lo /M2 control immunological tolerance (10, 11).…”