Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion

• Published in: Nature immunology Vol. 22; no. 2; pp. 205 - 215
• Main Authors: Scharping, Nicole E., Rivadeneira, Dayana B., Menk, Ashley V., Vignali, Paolo D. A., Ford, B. Rhodes, Rittenhouse, Natalie L., Peralta, Ronal, Wang, Yiyang, Wang, Yupeng, DePeaux, Kristin, Poholek, Amanda C., Delgoffe, Greg M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2021; Nature Publishing Group
• Subjects: 631/250/1619/554/1834/1269; 631/250/2152/569/2495; 631/250/2502; 631/250/580; Animals; Biomedical and Life Sciences; Biomedicine; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell differentiation; Cell Line, Tumor; Cell metabolism; Coculture Techniques; Energy Metabolism; Epigenetics; Female; Health aspects; HEK293 Cells; Humans; Hypoxia; Immunological research; Immunology; Immunotherapy; Infectious Diseases; Lymphocyte Activation; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mitochondria - immunology; Mitochondria - metabolism; NF-AT protein; Oxidative stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Physiological aspects; Positive Regulatory Domain I-Binding Factor 1 - genetics; Positive Regulatory Domain I-Binding Factor 1 - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction; T cell receptors; T cells; Transcription factors; Tumor Hypoxia; Tumor Microenvironment; United States
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-00834-9

Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8 + T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell–intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion.