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) α-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.
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Martin, P.J. et al. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 66, 664–672 (1985).
Curtis, R.E. et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 94, 2208–2216 (1999).
Kolb, H.J. et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76, 2462–2465 (1990).
Molldrem, J.J. et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat. Med. 6, 1018–1023 (2000).
Horowitz, M.M. et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990).
Truitt, R.L. & Johnson, B.D. Principles of graft-vs.-leukemia reactivity. Biol. Blood Marrow Transplant. 1, 61–68 (1995).
Weiden, P.L. et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N. Engl. J. Med. 300, 1068–1073 (1979).
Ferrara, J., Deeg, H.J. & Burakoff, S.J. Graft-vs.-Host Disease (Marcel Dekker, New York, 1997).
Ho, V.T. & Soiffer, R.J. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 98, 3192–3204 (2001).
Siadak, M. & Sullivan, K.M. The management of chronic graft-versus-host disease. Blood Rev. 8, 154–160 (1994).
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Shevach, E.M. Certified professionals: CD4+CD25+ suppressor T cells. J. Exp. Med. 193, F41–46 (2001).
Shevach, E.M., Thornton, A. & Suri-Payer, E. T lymphocyte-mediated control of autoimmunity. Novartis Found. Symp. 215, 200–211, 211–230 (1998).
Shevach, E.M. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Annacker, O. et al. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J. Immunol. 166, 3008–3018 (2001).
Murakami, M., Sakamoto, A., Bender, J., Kappler, J. & Marrack, P. CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc. Natl. Acad. Sci. USA 99, 8832–8837 (2002).
Kingsley, C.I., Karim, M., Bushell, A.R. & Wood, K.J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).
Field, E.H. et al. CD4+CD25+ regulatory cells in acquired MHC tolerance. Immunol. Rev. 182, 99–112 (2001).
Taylor, P.A., Lees, C.J. & Blazar, B.R. The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493–3499 (2002).
Cohen, J.L., Trenado, A., Vasey, D., Klatzmann, D. & Salomon, B.L. CD4+CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease. J. Exp. Med. 196, 401–406 (2002).
Hoffmann, P., Ermann, J., Edinger, M., Fathman, C.G. & Strober, S. Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J. Exp. Med. 196, 389–399 (2002).
Hakim, F.T.M. & Crystal, L. The immune system: effector and target of graft-versus-host disease. in Graft-vs-Host Disease (eds. Ferrara, J.L.M., Deeg, H.J. & Burakoff, S.J.) 257–289 (Marcel Dekker Inc., New York, 1997).
Sprent, J., Schaefer, M., Lo, D. & Korngold, R. Properties of purified T cell subsets. II. In vivo responses to class I vs. class II H-2 differences. J. Exp. Med. 163, 998–1011 (1986).
Contag, P.R., Olomu, I.N., Stevenson, D.K. & Contag, C.H. Bioluminescent indicators in living mammals. Nat. Med. 4, 245–247 (1998).
Contag, C.H., Jenkins, D., Contag, P.R. & Negrin, R.S. Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia 2, 41–52 (2000).
Costa, G.L. et al. Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit. J. Immunol. 167, 2379–2387 (2001).
Sweeney, T.J. et al. Visualizing the kinetics of tumor-cell clearance in living animals. Proc. Natl. Acad. Sci. USA 96, 12044–12049 (1999).
Edinger, M. et al. Noninvasive assessment of tumor cell proliferation in animal models. Neoplasia 1, 303–310 (1999).
Edinger, M. et al. Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood 101, 640–648 (2003).
Schmaltz, C. et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 97, 2886–2895 (2001).
Warnke, R.A. et al. The pathology and homing of a transplantable murine B cell leukemia (BCL1). J. Immunol. 123, 1181–1188 (1979).
Zeng, D. et al. Unique patterns of surface receptors, cytokine secretion, and immune functions distinguish T cells in the bone marrow from those in the periphery: impact on allogeneic bone marrow transplantation. Blood 99, 1449–1457 (2002).
Ferrara, J.L., Levy, R. & Chao, N.J. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol. Blood Marrow Transplant. 5, 347–356 (1999).
Krenger, W., Hill, G.R. & Ferrara, J.L. Cytokine cascades in acute graft-versus-host disease. Transplantation 64, 553–558 (1997).
Thornton, A.M. & Shevach, E.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).
Ermann, J. et al. CD4+CD25+ T cells facilitate the induction of T cell anergy. J. Immunol. 167, 4271–4275 (2001).
Piccirillo, C.A. & Shevach, E.M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J. Immunol. 167, 1137–1140 (2001).
Annunziato, F. et al. Phenotype, localization, and mechanism of suppression of CD4+CD25+ human thymocytes. J. Exp. Med. 196, 379–387 (2002).
Teshima, T. et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat. Med. 8, 575–581 (2002).
Suri-Payer, E., Amar, A.Z., Thornton, A.M. & Shevach, E.M. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 160, 1212–1218 (1998).
Dieckmann, D., Bruett, C.H., Ploettner, H., Lutz, M.B. & Schuler, G. Human CD4+CD25+ regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J. Exp. Med. 196, 247–253 (2002).
Morrison, S.J. & Weissman, I.L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).
Ailles, L. et al. Molecular evidence of lentiviral vector-mediated gene transfer into human self-renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cells. Mol. Ther. 6, 615–626 (2002).
We thank C. Arber for assistance with stem cell isolation, L. Ailles for the lentiviral vector constructs and C.H. Contag for access to the imaging equipment. This work was supported in part by NIH grants P01-CA49605, HL57443 and RO1s CA8006, HL58520, CA92225, CA65237, DK61925 and AI49903, and by fellowship grants from the Clinique LaPrairie Research Foundation (P.H.) and the Dr. Mildred Scheel Stifung (M.E.).
The authors declare no competing financial interests.
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Edinger, M., Hoffmann, P., Ermann, J. et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9, 1144–1150 (2003). https://doi.org/10.1038/nm915
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