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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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“Mitochondrial dysfunction is an inherent characteristic of functional exhausted T cells, which undergo reprogramming towards glycolysis, albeit their glycolytic ability is also reduced, compared to effector T cells [67, 68].”
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Mitochondria during T cell aging
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“Similarly to the observations of in vitro stimulated human T cells (126), transcriptional analysis during TEX development in response to LCMV infection revealed enrichment of genes involved in OXPHOS, particularly CPT1A (197).”
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Zhao, S., Peralta, R. M., Avina-Ochoa, N., Delgoffe, G. M., & Kaech, S. M. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101485 · Cited by 58
Self-citationThe Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection
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“Thus, these aberrations appear to reflect highmTOR activity as is consistent with the known role for chronic mTOR activation in promoting PD-1 up-regulation and downstreammetabolic changes that engender T cell exhaustion (27).”
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Self-citationThe double-edged sword: Harnessing PD-1 blockade in tumor and autoimmunity
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“Additionally, when effector T cells are activated, PD-1 signaling inhibits glycolysis and induces OXPHOS dysregulation by interrupting AKT phosphorylation and recruiting SHP1/ 2 phosphatase to inhibit PI3K activation before T cells show significant incapacitation (Parry et al., 2005; Bengsch et al., 2016; Ogando et al…”
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“changes compared with effector T cells [86, 90].”
BackgroundResultInfluentialClonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis
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Association of TIM-3 expression with glucose metabolism in Jurkat T cells
Lee, M. J., Yun, S. J., Lee, B., Jeong, E., Yoon, G., Kim, K. H., & Park, S. (2020) · BMC Immunology · doi:10.1186/s12865-020-00377-6 · Cited by 47
PD-L1 and B7-1 Cis-Interaction: New Mechanisms in Immune Checkpoints and Immunotherapies
Nishimura, C., Pulanco, M. C., Cui, W., Lu, L., & Zang, X. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.10.004 · Cited by 45
Tuberculosis endotypes to guide stratified host-directed therapy
DiNardo, A. R., Nishiguchi, T., Grimm, S. L., Schlesinger, L. S., Graviss, E. A., Cirillo, J. D., Coarfa, C., Mandalakas, A. M., Heyckendorf, J., Kaufmann, S. H. E., et al. (2021) · Med · doi:10.1016/j.medj.2020.11.003 · Cited by 47
Reversing T-cell exhaustion in immunotherapy: a review on current approaches and limitations
Tabana, Y., Moon, T. C., Siraki, A. G., Elahi, S., & Barakat, K. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1937123 · Cited by 47
“Anti–PD-1 blockade also leads to changes in the metabolic reprogramming, which mediates T-cell reinvigoration [101].”
BackgroundCribioli, E., Attianese, G. M. P. G., Ginefra, P., Signorino-Gelo, A., de Silly, R. V., Vannini, N., Hess, C., Irving, M. B., & Coukos, G. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.976628 · Cited by 44
“Similarly, in a chronic infection model, early exhausted T cells demonstrated impaired glycolytic and mitochondrial metabolism and comprised depolarized mitochondria (42).”
BackgroundChen, Y., Liu, Z., Lin, Z., Lu, M., Fu, Y., Liu, G., & Yu, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1219895 · Cited by 46
Sugar or Fat?—Metabolic Requirements for Immunity to Viral Infections
Shehata, H. M., Murphy, A. J., Lee, M. K. S., Gardiner, C. M., Crowe, S. M., Sanjabi, S., Finlay, D. K., & Palmer, C. S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01311 · Cited by 47
Rodrigues, N. V., Correia, D. V., Mensurado, S., Pereira, S. N., deBarros, A., Kyle‐Cezar, F., Tutt, A. N. J., Hayday, A., Norell, H., Silva‐Santos, B., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0327 · Cited by 48
Fisicaro, P., Boni, C., Barili, V., Laccabue, D., & Ferrari, C. I. (2018) · Current Opinion in Virology · doi:10.1016/j.coviro.2018.01.003 · Cited by 44
Regulation of T cell immunity by cellular metabolism
Hu, Z., Zou, Q., & Su, B. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0668-2 · Cited by 43
Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus
Kahan, S. M., & Zajac, A. J. (2019) · Viruses · doi:10.3390/v11020156 · Cited by 44
Reversing Post-Infectious Epigenetic-Mediated Immune Suppression
Abhimanyu, A., Ontiveros, C. O., Guerra-Resendez, R. S., Nishiguchi, T., Ladki, M., Hilton, I. B., Schlesinger, L. S., & DiNardo, A. R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.688132 · Cited by 46
Protein Arginine Methylation: An Emerging Modification in Cancer Immunity and Immunotherapy
Dai, W., Zhang, J., Li, S., He, F., Liu, Q., Gong, J., Yang, Z., Gong, Y. Q., Tang, F., Wang, Z., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.865964 · Cited by 49
More TOR: The expanding role of mTOR in regulating immune responses
Patel, C. H., & Powell, J. D. (2025) · Immunity · doi:10.1016/j.immuni.2025.06.010 · Cited by 48
T cell metabolism in chronic viral infection
Pallett, L. J., Schmidt, N. M., & Schurich, A. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13308 · Cited by 44
Mitochondria orchestrate T cell fate and function
Liu, X., & Peng, G. (2021) · Nature Immunology · doi:10.1038/s41590-020-00861-6 · Cited by 43
T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective
Peters, F. S., Strefford, J. C., Eldering, E., & Kater, A. P. (2021) · Haematologica · doi:10.3324/haematol.2020.267914 · Cited by 43
The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate
Weisshaar, N., Ma, S., Ming, Y., Madi, A., Mieg, A., Hering, M., Zettl, F., Möhr, K., ten Bosch, N., Stichling, D., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01636-5 · Cited by 43
“No statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported in previous publications 2,55 .”
BackgroundMethodT cell exhaustion in human cancers
Kang, K., Lin, X., Chen, P., Liu, H., Liu, F., Xiong, W., Li, G., Yi, M., Li, X., Wang, H., et al. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189162 · Cited by 49
Zinser, M. E., Highton, A. J., Kurioka, A., Kronsteiner, B., Hagel, J., Leng, T., Marchi, E., Phetsouphanh, C., Willberg, C. B., Dunachie, S. J., et al. (2018) · Immunology and Cell Biology · doi:10.1111/imcb.12020 · Cited by 42
“Depolarization of mitochondria was assessed by staining with MitoTracker DeepRed, which preferentially accumulates within healthy polarized mitochondria.(18,19) MAIT cells showed similar mitochondrial depolarization compared to most CD8 T cells (Figure 1c, d) whereas TEM showed a significantly higher frequency of cell…”
MethodShaw, T. D., Krasnodembskaya, A. D., Schroeder, G. N., Zumla, A. I., Maeurer, M. J., & O’Kane, C. M. (2021) · Clinical Microbiology Reviews · doi:10.1128/cmr.00064-21 · Cited by 43
The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity
He, Y., Vlaming, M., van Meerten, T., & Bremer, E. (2022) · Cancers · doi:10.3390/cancers14020299 · Cited by 40
“Thus, HVEM co-stimulation appears to increase energy metabolism, a feature positively related to reduced T cell exhaustion [120,121].”
BackgroundManipulating T-cell metabolism to enhance immunotherapy in solid tumor
Chen, C., Wang, Z., Ding, Y., & Qin, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1090429 · Cited by 43
Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function
Edwards-Hicks, J., Apostolova, P., Buescher, J. M., Maib, H., Stanczak, M. A., Corrado, M., Geltink, R. I. K., Maccari, M. E., Villa, M., Carrizo, G., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01419-y · Cited by 43
Self-citationMetabolic rewiring and communication in cancer immunity
Chapman, N. M., & Chi, H. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.02.001 · Cited by 44
Early effector maturation of naïve human CD8+ T cells requires mitochondrial biogenesis
Fischer, M., Bantug, G. R., Dimeloe, S., Gubser, P. M., Burgener-Gasser, A.-V., Grählert, J., Balmer, M. L., Develioglu, L., Steiner, R., Unterstab, G., et al. (2018) · European Journal of Immunology · doi:10.1002/eji.201747443 · Cited by 41
Zhang, E., Ma, Z., Li, Q., Yan, H., Liu, J., Wu, W., Guo, J., Zhang, X., Kirschning, C. J., Xu, H. C., et al. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900065 · Cited by 41
“PD-L1/PD-1–induced T cell exhaustion was related to glycolytic and mitochondrial alterations, resulting in bioenergetic insufficiency of viral-specific CD8 T cells (53, 54).”
BackgroundMetabolic Traits in Cutaneous Melanoma
Neagu, M. T. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00851 · Cited by 43
“In effector T cells, immune therapy with immune checkpoint blockade turns back the cell’s metabolism to glycolysis (44, 45).”
BackgroundJohnson, R. L., Cummings, M., Thangavelu, A., Theophilou, G., Jong, D. D., & Orsi, N. M. (2021) · Cancers · doi:10.3390/cancers13246231 · Cited by 39
Metabolic dynamics instruct CD8 + T‐cell differentiation and functions
Bevilacqua, A., Li, Z., & Ho, P. (2022) · European Journal of Immunology · doi:10.1002/eji.202149486 · Cited by 41
A variety of ‘exhausted’ T cells in the tumor microenvironment
Nagasaki, J., & Togashi, Y. (2022) · International Immunology · doi:10.1093/intimm/dxac013 · Cited by 43
Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review
Kiran, D., & Basaraba, R. J. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.624607 · Cited by 39
How metabolism bridles cytotoxic CD8+ T cells through epigenetic modifications
Acker, H. H. V., Ma, S., Scolaro, T., Kaech, S. M., & Mazzone, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.03.006 · Cited by 39
CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement
Pant, A., & Lim, M. K. (2023) · Cancers · doi:10.3390/cancers15041249 · Cited by 39
“Adopting similar strategies in CAR-T cells against GBM can help prevent metabolic exhaustion, which precedes phenotypic exhaustion [55].”
MethodRegulation of mTOR, Metabolic Fitness, and Effector Functions by Cytokines in Natural Killer Cells
Viel, S., Besson, L., Marotel, M., Walzer, T., & Marçais, A. (2017) · Cancers · doi:10.3390/cancers9100132 · Cited by 38
“T cell mitochondrial biogenesis was repressed via Akt-mediated inhibition of PGC-1α [10].”
BackgroundAdaptive Immune Response against Hepatitis C Virus
Kemming, J. S., Thimme, R., & Neumann‐Haefelin, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165644 · Cited by 40
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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