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Central Memory CD8⁺ T Cells Induce Graft-versus-Host Disease and Mediate Graft-versus-Leukemia¹

Hong Zheng^*, Catherine Matte-Martone, Dhanpat Jain, Jennifer McNiff and Warren D. Shlomchik^2,

^* Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033; and Yale Cancer Center and Department of Immunobiology, Department of Pathology, and Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520

In allogeneic hemopoietic stem cell transplantation, mature donor β T cells in the allograft promote T cell reconstitution in the recipient and mediate the graft-vs-leukemia (GVL) effect. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-vs-host disease (GVHD). It has previously been shown that effector memory T cells not primed to alloantigen do not cause GVHD yet transfer functional T cell memory and mediate GVL. Recently, central memory T cells (T_CM) have also been reported to not cause GVHD. In contrast, in this study, we demonstrate that purified CD8⁺ T_CM not specifically primed to alloantigens mediate GVHD in the MHC-mismatched C57BL/6 (B6)BALB/c and the MHC-matched, multiple minor histocompatibility Ag-mismatched C3H.SWB6 strain pairings. CD8⁺ T_CM and naive T cells (T_N) caused similar histological disease in liver, skin, and bowel. B6 CD8⁺ T_CM and T_N similarly expanded in BALB/c recipients, and the majority of their progeny produced IFN- upon restimulation. However, in both models, CD8⁺ T_CM induced milder clinical GVHD than did CD8⁺ T_N. Nonetheless, CD8⁺ T_CM and T_N were similarly potent mediators of GVL against a mouse model of chronic-phase chronic myelogenous leukemia. Thus, in contrast to what was previously thought, CD8⁺ T_CM are capable of inducing GVHD and are substantially different from T_EM but only subtly so from T_N.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01-CA96943 and R01-HL 066279. W.D.S. is a recipient of a Clinical Scholar Award from the Leukemia and Lymphoma Society. H.Z. was a recipient of Christian Jacobsen Postdoctoral Fellowship Award from the Marrow Foundation and the National Marrow Donor Program.

² Address correspondence and reprint requests to Dr. Warren D. Shlomchik, Yale Comprehensive Cancer Center, P.O. Box 208032, Yale University School of Medicine, New Haven, CT 06520-8032. E-mail address: warren.shlomchik{at}yale.edu

³ Abbreviations used in this paper: alloSCT, allogeneic hemopoietic stem cell transplantation; GVHD, graft-vs-host disease; GVL, graft-vs-leukemia; LN, lymph node; mCP-CML, mouse model of chronic-phase CML; miHA, multiple minor histocompatibility Ag; NGFR, nerve growth factor receptor; PB, peripheral blood; PP, Peyer’s patch; TCD, T cell depleted; T_CM, central memory T cell; T_EM, effector memory T cell; T_N, naive T cell; mCP-CML, mouse model of chronic-phase chronic myelogenous leukemia.

⁴ The online version of this article contains supplemental material.