CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation.
Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4+CD25+ regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4+CD25+ regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) alpha-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4+CD25+ T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells.
Edinger
Matthias
M
Division of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Hoffmann
Petra
P
Ermann
Joerg
J
Drago
Kathryn
K
Fathman
C Garrison
CG
Strober
Samuel
S
Negrin
Robert S
RS
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D007938:Leukemia / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008223:Lymphoma / Q000628:therapy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018123:Receptors, Interleukin / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology / Q000379:methods
C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D054353:Perforin; D007371:Interferon-gamma