Naturally Arising Memory-Phenotype CD4+ T Lymphocytes Give Rise to Multiple Helper Subsets to Contribute to Tumor Immunity while Inhibiting GVHD

Memory-phenotype (MP) CD4+ T lymphocytes spontaneously develop in steady state from peripheral naïve precursors in a manner dependent on self-antigen recognition. Although MP cells possess innate type 1 and 3 effector functions that can contribute to host defense and autoimmunity, their immunologic functions in tumor immunity and GVHD, which results from therapeutic bone marrow transplantation (BMT) against hematologic malignancies, remain unclear. In this study, we show that in mixed lymphocyte reactions, MP lymphocytes can generate Th1, Th17, and regulatory T (Treg) cell subsets, whereas naïve cells dominantly differentiate to Th1. Consistent with this, naïve lymphocytes mainly induce Th1 responses in the mouse EL4 model of malignant lymphoma and the B16 model of malignant melanoma, whereas MP cells efficiently give rise to Th1, Th17, and Treg cell subsets to exert mild, IFN-γ-dependent antitumor activities in vivo. Moreover, we demonstrate using a mouse model of BMT that MP cells more efficiently differentiate into Treg cells to partially suppress GVHD as compared to naïve T lymphocytes. Furthermore, our data suggest that when used as donor T lymphocytes in BMT in tumor-bearing mice, MP cells give rise to Th1, Th17, and Treg cells to generate antitumor responses without inducing GVHD. Together, these results identify MP cells as a unique T-cell population that has the potential to generate multiple Th subsets including Th1 and Treg cells, thereby contributing to tumor immunity while inhibiting the development of BMT-associated GVHD.