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Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8 + T Cell Exhaustion
Open accessAbstract
Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.
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“Repression of PGC1α, an important cofactor of NRF1 activity, is an early event in T cell exhaustion, indicating a mechanistic overlap between T cell aging and exhaustion”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Bengsch et al., 2016
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Okoye, I., Wang, L., Pallmer, K., Richter, K., Ichimura, T., Haas, R., Crouse, J., Choi, O., Heathcote, D. A., Lovo, E., et al. (2015) · Science · doi:10.1126/science.aaa7516 · Cited by 51 · cited 1×
“In support of this notion, improving mitochondrial OXPHOS by overexpression or gain-of-function of lymphocyte expansion molecule (lem) increased virus-specific T cell function and viral control early during clone 13 infection (Okoye et al., 2015).”
BackgroundRetractedSubramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · cited 1×
“GSEA used gene sets from the Molecular Signature Database v.5.0 (Subramanian et al., 2005) including KEGG pathway gene lists obtained from http://www.genome.jp/kegg/pathway.html.”
MethodInfluentialMolecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652 · cited 3×
“Tex cells are defined by poor effector functions, high co-expression of multiple inhibitor receptors and an altered global transcriptional program compared to functional Teff or Tmem cells (Wherry and Kurachi, 2015).”
BackgroundSelf-citationRestoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057 · cited 1×
“PD-L1 blockade resulted in an expansion of virusspecific T cells associated with lower viral load (data not shown), as previously described (Barber et al., 2006).”
ResultSelf-citationPosttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204 · cited 3×
“In addition, switching to glycolysis is directly linked to increased effector function (Chang et al., 2013; Ho et al., 2015).”
BackgroundResultMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103 · cited 3×
“Differences between in vitro studies and the current data might be due to differences between in vitro activated Teff-like cells and in vivo generated Tex cells that are transcriptionally and phenotypically distinct from Teff cells (Doering et al., 2012; Wherry et al., 2007).”
BackgroundResultSelf-citationCheckpoint blockade cancer immunotherapy targets tumour-specific mutant antigens
Gubin, M. M., Zhang, X., Schuster, H., Caron, E., Ward, J. P., Noguchi, T., Ivanova, Y., Hundal, J., Arthur, C. D., Krebber, W.-J., et al. (2014) · Nature · doi:10.1038/nature13988 · Cited by 1,974 · cited 2×
“PD-1 blockade in tumor models is associated with transcriptional changes in metabolic genes (Gubin et al., 2014).”
BackgroundCTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms
Parry, R. V., Chemnitz, J. M., Frauwirth, K. A., Lanfranco, A. R., Braunstein, I., Kobayashi, S. V., Linsley, P. S., Thompson, C. B., & Riley, J. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9543-9553.2005 · Cited by 1,931 · cited 1×
“The intracellular tail of PD-1 contains an immunotyrosine inhibitorymotif (ITIM) and an immunotyrosine switchmotif (ITSM), that can recruit phosphatases such as SHP-2, allowing dephosphorylation of key signal transducers (Chemnitz et al., 2004; Okazaki et al., 2001).”
BackgroundmTOR regulates memory CD8 T-cell differentiation
Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., Larsen, C. P., & Ahmed, R. (2009) · Nature · doi:10.1038/nature08155 · Cited by 1,575 · cited 3×
“This treatmentmildly reduced the number of virus-specific T cells (Figures 4B and 4C) as expected based on the role of mTOR in effector CD8+ T cell expansion (Araki et al., 2009; Pearce et al., 2009).”
BackgroundEnhancing CD8 T-cell memory by modulating fatty acid metabolism
Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y. (2009) · Nature · doi:10.1038/nature08097 · Cited by 1,559 · cited 1×
“This treatmentmildly reduced the number of virus-specific T cells (Figures 4B and 4C) as expected based on the role of mTOR in effector CD8+ T cell expansion (Araki et al., 2009; Pearce et al., 2009).”
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“Its increased expression on T-cells indicates a critical stage of T-cell development, at the verge of going in retraction and clearance (109, 112).”
BackgroundPatwardhan, R. S., Gohil, D., Singh, B., Kumar, B. K., Purohit, V., Thoh, M., Checker, R., Gardi, N., Gota, V., Kutala, V. K., et al. (2024) · Phytotherapy Research · doi:10.1002/ptr.8126 · Cited by 8
Metabolic Regulation of T Cell Exhaustion
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Mai, L. T., Swaminathan, S., Nguyen, T. H., Collette, É., Charpentier, T., Carmona‐Pérez, L., Loucif, H., Lamarre, A., Heinonen, K. M., Langlais, D., et al. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00485-2 · Cited by 8
“At the early stages of exhaustion, Tex show a limited glucose uptake and a decline in glycolysis, which is ascribed to an elevated expression of PD-1 (Bengsch et al, 2016; Patsoukis et al, 2015).”
InfluentialZecca, A., Barili, V., Olivani, A., Biasini, E., Boni, C., Fisicaro, P., Montali, I., Tiezzi, C., Valle, R. D., Ferrari, C. I., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.875072 · Cited by 11
“A similar discrepancy between metabolic, functional, and gene expressions that could reflect a failed compensatory attempt has been described in exhausted CD8+ T cells (42).”
BackgroundModulatory Role of Phytochemicals/Natural Products in Cancer Immunotherapy
Vijayan, Y., Sandhu, J. S., & Harikumar, K. B. (2024) · Current Medicinal Chemistry · doi:10.2174/0109298673274796240116105555 · Cited by 8
Feeling Worn Out? PGC1α to the Rescue for Dysfunctional Mitochondria in T Cell Exhaustion
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“Two related studies by Bengsch et al. and Scharping et al., published in the current issue of Immunity, now shed light on this important aspect of T cell exhaustion, specifically in CD8+ T cells (Bengsch et al., 2016; Scharping et al., 2016).”
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JunB is required for CD8+ T cell responses to acute infections
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Epigenetic reprogramming holds promise in enhancing anti-tumor efficacy of CAR T cell therapy
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SUMOylation is destined for regulatory T cell-related immune dysregulation
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Mitochondrial Exhaustion of Memory CD4 T-Cells in Treated HIV-1 Infection
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Regulation of immune cell metabolism by cancer cell oncogenic mutations
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Gene expression signatures identify biologically and clinically distinct tuberculosis endotypesPreprint
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Akiso, M., Ameka, M., Naidoo, K. K., Langat, R., Kombo, J., Sikuku, D., Ndung’u, T., Altfeld, M. A., Anzala, O. A., & Mureithi, M. (2023) · PLoS ONE · doi:10.1371/journal.pone.0286436 · Cited by 6
Reversal of T-cell exhaustion: Mechanisms and synergistic approaches
Hu, Y., Zhang, Y., Shi, F., Yang, R., Yan, J., Han, T., & Guan, L. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112571 · Cited by 9
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“Briefly, upstream molecular pathways, such as mTOR and TGF β (85), PD1 signaling (86) and IL‑10 stimulation (87), orchestrate the activities of transcription factors myelo‑ blastosis (88), activator protein 1 (61,89), BATF (90‑92), BTB and CNC Homology 2 (BACH2) (90), special AT‑rich…”
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“Mitochondrial homeostasis and energy metabolism are critical for controlling T cell function [25, 70, 71].”
Immunometabolism in the Bladder Cancer Microenvironment
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Redox regulation of defense against bacterial and viral pathogens
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Defective mitochondria disrupt CD8+ T cells
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The potential combinational immunotherapiesfor treatment of hepatocellular carcinoma
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“However, the tumour-in fi ltrating T cells are often exhausted (Jiang, Li, & Zhu, 2015) due to the decrease in mitochondrial biosynthesis and dysfunctional metabolism (Bengsch et al., 2016; Scharping et al., 2016).”
Co-inhibitory receptors, transcription factors and tolerance
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Metadata
- Authors
- Bengsch, B., Johnson, A. L., Kurachi, M., Odorizzi, P. M., Pauken, K. E., Attanasio, J., Stelekati, E., McLane, L. M., Paley, M. A., Delgoffe, G. M., & Wherry, E. J.
- Affiliations
- University of Pennsylvania (US)
- UPMC Hillman Cancer Center (US)
- Corresponding author
- Wherry, E. John
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 45
- Issue
- 2
- Pages
- 358-373
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4988919
- OpenAlex
- W2478467838
- Cited by
- 868
- References
- 40
- Citations by year
- 2026: 127 · 2025: 87 · 2024: 93 · 2023: 89 · 2022: 92 · 2021: 107 · 2020: 85 · 2019: 63 · 2018: 59 · 2017: 55 · 2016: 10
- FWCI
- 33.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA121973, P50CA097190)
- National Institute of Allergy and Infectious Diseases (R01AI115712, R01AI105343, P01AI112521, R21AI117718, U01AI095608, U19AI082630, P01AI108545)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- PD-1, CD8+ T cell exhaustion, glycolysis, mitochondrial metabolism, PGC-1α, mTOR signaling, glucose uptake, chronic viral infection, lymphocytic choriomeningitis virus, PD-L1 blockade, immune checkpoint blockade
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Cells, Cultured, Energy Metabolism, Glucose, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Signal Transduction, Cellular Senescence, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice, Antibodies, Neutralizing, TOR Serine-Threonine Kinases, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Cellular Reprogramming
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