APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease.
Host APCs are required for initiating T cell-dependent acute graft-vs-host disease (GVHD), but the role of APCs in the effector phase of acute GVHD is not known. To measure the effect of tissue-resident APCs on the local development of acute GVHD, we selectively depleted host macrophages and DCs from the livers and spleens, but not from the skin, peripheral lymph nodes (PLN), or mesenteric lymph nodes (MLN), of C57BL/6 (B6) mice by i.v. administration of liposomal clodronate before allogeneic bone marrow transplantation. Depletion of host hepatic and splenic macrophages and DCs significantly inhibited the proliferation of donor C3H.SW CD8(+) T cells in the spleen, but not in the PLN or MLN, of B6 mice. Such organ-selective depletion of host tissue APCs also markedly reduced the trafficking of allogeneic CD8(+) T cells into the livers and spleens, but not PLN and MLN, of B6 recipients compared with that of the control mice. Acute hepatic, but not cutaneous, GVHD was inhibited as well, resulting in improved survival of liposomal clodronate-treated B6 recipients. When C3H.SW CD8(+) T cells were activated in normal B6 recipients, recovered, and adoptively transferred into secondary B6 recipients, activated donor CD8(+) T cells rapidly migrated into the livers and spleens of control B6 recipients but were markedly decreased in B6 mice that were depleted of hepatic and splenic macrophages and DCs. Thus, tissue-resident APCs control the local recruitment of allo-reactive donor T cells and the subsequent development of acute GVHD.
Zhang
Yi
Y
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Shlomchik
Warren D
WD
Joe
Gerard
G
Louboutin
Jean-Pierre
JP
Zhu
Jiang
J
Rivera
Adam
A
Giannola
Diane
D
Emerson
Stephen G
SG
D000208:Acute Disease; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D004002:Clodronic Acid / Q000008:administration & dosage; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007275:Injections, Intravenous; D008081:Liposomes; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D015996:Survival Rate
D007166:Immunosuppressive Agents; D008081:Liposomes; D004002:Clodronic Acid