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CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation

Abstract

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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Figure 1: CD4+CD25+ Treg cells suppress alloreactivity in vitro and in vivo.
Figure 2: CD25 expression and cytokine production of donor T cells 5 d after transplantation.
Figure 3: Treg cells do not abrogate cytotoxic activity of Tconv cells against A20 leukemia cells in vitro.
Figure 4: GVT activity is maintained in the presence of Treg cells.
Figure 5: Protection from GVHD by donor Treg cells allows cotransplantation of sufficient numbers of effector T cells for GVT activity.

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Acknowledgements

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.).

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Correspondence to Robert S Negrin.

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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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