Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease.

Allogeneic CD8+ T cells mediate both a graft-vs-leukemia (GVL) effect and graft-vs-host disease (GVHD). To evaluate whether CD8 cells of defined cytokine phenotype differentially mediate these processes, alloreactive donor CD8+ T cells preferentially secreting type I or type II cytokines were generated by alloantigenic priming in vitro in the presence of IL-12 or IL-4, respectively. Both cytokine-secreting subsets lysed allogeneic tumor targets in vitro ("Tc1" and "Tc2" subsets). A transplantation model was established (B6 into B6C3F1, 1050 cGy host irradiation) using the 32Dp210 myeloid line (bcr/abl transfected, H-2k; 1 x 10(4) tumor cells/recipient). Compared with leukemia controls (death at 12.9 days post-bone marrow transplantation), both Tc1 and Tc2 recipients were conferred a survival advantage. At cell doses of 2 to 2.5 x 10(7), the Tc1-mediated GVL effect (mean survival of 34.2 days) was more potent than the Tc2-mediated GVL effect (mean survival of 20.5 days; Tc1 > Tc2, p = 0.009). On day 15, histologic examination showed that Tc1 recipients had undetectable tumor burdens, whereas Tc2 recipients had extensive leukemic infiltrates. However, Tc2 recipients had essentially no histologic evidence of GVHD, whereas Tc1 recipients had mild to moderate GVHD (average GVHD scores of 1/40 and 9.3/40, respectively). In contrast, recipients of uncultured CD8+ donor T cells developed severe GVHD (average GVHD score of 26.7/40). Because in vitro-generated, alloreactive Tc1 and Tc2 populations mediated GVL with reduced GVHD, we conclude that both subsets may improve the therapeutic outcome of allogeneic T cell transfers in patients with leukemia.

Allospecific CD4+, Th1/Th2 and CD8+, Tc1/Tc2 populations in murine GVL: type I cells generate GVL and type II cells abrogate GVL.

Donor CD4+ and CD8+ T cells mediate graft-vs.-leukemia (GVL) responses in the allogeneic bone marrow transplantation (alloBMT) setting. To evaluate the role of functional T cell subsets in the mediation of GVL, alloreactive donor CD4+ (Th1/Th2) and CD8+ (Tc1/Tc2) T cells of defined cytokine phenotype were generated by in vitro culture. A leukemia/transplantation model (B6 into B6C3F1; 1050 cGy host irradiation) was established using the bcr/abl-transfected myeloid leukemia line, 32Dp210 (P210; H-2k). Leukemia control mice (1X10(4) P210 cells per recipient) died at day 12.0 post-BMT. Recipients of the CD4+, Th1-type or CD8+, Tc1-type populations were conferred a survival advantage (death at 20.7 and 23.5 days post-BMT, respectively). In contrast, the CD4+, Th2-type population did not mediate GVL (death at 12.3 days). Furthermore, cell mixing experiments demonstrated that the Th2 subset abrogated both Th1- and Tc1-mediated GVL. The CD8+, Tc2 population, which secreted type II cytokines and lysed the P210 leukemia target in vitro, mediated GVL in some experiments; interestingly, the magnitude of Tc2-mediated GVL was inversely related to the level of interleukin-10 (IL-10) secreted in vitro by the Tc2 population. These studies therefore indicate that alloreactive T cells of type I phenotype maximally generate GVL, and that type I/type II interactions are an important consideration for allogeneic transplantation in the setting of leukemic hosts.