Central memory CD8⁺ T cells induce graft-versus-host disease and mediate graft-versus-leukemia

In allogeneic hemopoietic stem cell transplantation, mature donor αβ 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.SW→B6 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-γ 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.