Efforts to overcome tolerance to improve adoptive immunotherapy for cancer have been hindered because the T cell intrinsic pathways that regulate whether tumor/self-reactive T cells are directed toward tolerance versus immunity remain largely undefined. Our lab studies a murine model of tolerance in which adoptively transferred tumor/self-reactive CD8+ T cells undergo multiple rounds of division following engagement of tumor/self-antigen, but fail to produce effector molecules and are progressively deleted without providing anti-tumor immunity. Here, we demonstrate that T cells engaging antigen within this tolerizing environment fail to express the T-box transcription factor, T-bet, which is induced under immunizing conditions. We further establish that restoring T-bet expression in these T cells within the tolerizing environment by vaccination with Listeria monocytogenes corresponds with their acquisition of effector function and the prolonged survival of leukemia-bearing hosts. Utilizing T-bet deficient T cells, we confirmed that T-bet is required for this rescue of effector function and for therapeutic anti-tumor immunity within a tolerizing environment. We are now utilizing T cells with constitutive T-bet expression to determine if T-bet alone is sufficient to overcome tolerance. Our results identify T-bet as a CD8+ T cell-intrinsic regulator of effector responses within a tolerizing environment and have important implications for immunotherapy in patients with cancer.
- Copyright © 2013 by The American Association of Immunologists, Inc.