Nelson et al. show that repeated acute infection with self-antigen-containing viruses reversed anergy in mouse models of CD8+ T cell tolerance to melanocyte protein gp100 and skin- or small intestine- expressed ovalbumin. Self-antigen-specific CD8+ memory-like T cells expanded and persisted in the absence of antigen in secondary- and non-lymphoid tissues, and exhibited thymic-independent TCR avidity maturation, and increased PD-1 levels. Peptide-stimulated CD8+ T cells produced IFNγ and TNFα ex vivo and mediated cytotoxicity in vivo. Immunization delayed growth of and controlled self-antigen-expressing B16 melanomas without autoimmunity.
Contributed by Paula Hochman
The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8(+) T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8(+) T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8(+) T cells that can be used for cancer treatment.
Author Info: (1) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (2)
Author Info: (1) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (2) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (3) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (4) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (5) Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55118, USA. (6) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (7) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. (8) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (9) Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: vvezys@umn.edu.
