Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease.
Skin is the most commonly affected organ in graft-versus-host disease (GVHD). To explore the role of Langerhans cells in GVHD, the principal dendritic cells of the skin, we studied the fate of these cells in mice transplanted with allogeneic bone marrow. In contrast to other dendritic cells, host Langerhans cells were replaced by donor Langerhans cells only when donor T cells were administered along with bone marrow, and the extent of Langerhans cell chimerism correlated with the dose of donor T cells injected. Donor T cells depleted host Langerhans cells through a Fas-dependent pathway and induced the production in skin of CCL20, which was required for the recruitment of donor Langerhans cells. Administration of donor T cells to bone marrow-chimeric mice with persistent host Langerhans cells, but not to mice whose Langerhans cells had been replaced, resulted in marked skin GVHD. These findings indicate a crucial role for donor T cells in host Langerhans cell replacement, and show that host dendritic cells can persist in nonlymphoid tissue for the duration of an animal's life and can trigger GVHD despite complete blood chimerism.
Merad
Miriam
M
Department of Pathology, Stanford University School of Medicine, Palo Alto, California 94304, USA. miriam.merad@mssm.edu
Hoffmann
Petra
P
Ranheim
Erik
E
Slaymaker
Sarah
S
Manz
Markus G
MG
Lira
Sergio A
SA
Charo
Israel
I
Cook
Donald N
DN
Weissman
Irving L
IL
Strober
Samuel
S
Engleman
Edgar G
EG
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D002678:Chimera / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007801:Langerhans Cells / Q000276:immunology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous; D014467:Ultraviolet Therapy
C515335:Ccr2 protein, mouse; D018925:Chemokines; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D054353:Perforin