Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a limiting factor in allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of leukemia and other malignancies. Relative to the process that initiates and promotes cGVHD, the regulation is poorly understood. In this study, we examined the role of naturally occurring regulatory dendritic cells (DC_regs) in murine major histocompatibility complex (MHC)-compatible and multiple minor histocompatibility antigen (miHAg)-incompatible model of cGVHD in alloHSCT. DC_regs generated from bone marrow in vitro (BM-DC_regs) exclusively expressed CD200 receptor 3 (CD200R3), which exerted a suppressive function in the Ag-specific CD4⁺ T-cell response. CD49⁺ CD200R3⁺ cells showed similarities in phenotype and function to BM-DC^regs, which formally distinguishes them from other leukocytes, suggesting that they are the natural counterpart of BM-DC_regs. Treatment of the recipient mice after alloHSCT with the recipient-type CD49 ⁺ CD200R3⁺ cells as well as BM-D_Cregs protected against cGVHD, and the protection was associated with the generation of Ag-specific anergic CD4⁺ T cells as well as CD4⁺CD25 ⁺Foxp3⁺ regulatory T cells (T_regs) from donor-derived alloreactive CD4⁺CD25^-Foxp3^- T cells. In addition, the depletion of CD49⁺CD200R3⁺ cells before alloHSCT enhanced the progression of cGVHD. In conclusion, CD49 ⁺ CD200R3⁺ cells act as naturally occurring D _Cregs to regulate the pathogenesis of cGVHD in alloHSCT mediated through the control of the transplanted alloreactive CD4⁺ T cells.