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-DC(regs) 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 DC(regs) to regulate the pathogenesis of cGVHD in alloHSCT mediated through the control of the transplanted alloreactive CD4(+) T cells.
Sato
Kaori
K
Laboratory for Dendritic Cell Immunobiology, RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan.
Eizumi
Kawori
K
Fukaya
Tomohiro
T
Fujita
Shigeharu
S
Sato
Yumiko
Y
Takagi
Hideaki
H
Yamamoto
Mai
M
Yamashita
Naohide
N
Hijikata
Atsushi
A
Kitamura
Hiroshi
H
Ohara
Osamu
O
Yamasaki
Sho
S
Saito
Takashi
T
Sato
Katsuaki
K
D000818:Animals; D001853:Bone Marrow; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D007962:Leukocytes / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012871:Skin Diseases / Q000276:immunology / Q000517:prevention & control*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
C492346:CD200 receptor, mouse; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse