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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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“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).”
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“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
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“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
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“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).”
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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).”
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“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
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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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CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?
Hoyt-Miggelbrink, A. M., Jackson, J. D., Lorrey, S., Srinivasan, E. S., Polania, J. W., Wilkinson, D. S., & Fecci, P. E. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0206 · Cited by 258
“The typical characteristics of CD8 T-cell exhaustion include antigen load– dependentandtemporallyprogressive lossofeffectoractivity(8,23,24), loss of proliferative capacity (25, 26), altered expression of transcription factors (27, 28), loss of antigen-independent homeostatic proliferation (29), and modified epigeneti…”
BackgroundMetabolic Control of CD8+ T Cell Fate Decisions and Antitumor Immunity
Zhang, L., & Romero, P. J. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.11.005 · Cited by 241
Moro‐García, M. A., Mayo, J. C., Sainz, R. M., & Alonso‐Arias, R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00339 · Cited by 241
T cell Allorecognition Pathways in Solid Organ Transplantation
Siu, J. H. Y., Surendrakumar, V., Richards, J. A., & Pettigrew, G. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02548 · Cited by 223
“Finally, although exhausted T cells exhibit typical aerobic glycolysis at initiation of the response, continued antigen binding to the TCR results in downregulation of the PI3K–AKT1–mTOR signaling pathway (139) and NFATC-mediated expression of PD-1 and other inhibitory ligands (140, 141).”
BackgroundCAR-T cell performance: How to improve their persistence?
López-Cantillo, G., Urueña, C., Camacho, B. A., & Ramírez-Segura, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.878209 · Cited by 207
Qiao, G., Bucsek, M. J., Winder, N. M., Chen, M., Giridharan, T., Olejniczak, S. H., Hylander, B. L., & Repasky, E. A. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2243-8 · Cited by 213
Ye, L., Park, J. J.-Y., Peng, L., Yang, Q., Chow, R. D.-W., Dong, M. B., Lam, S. Z., Guo, J., Tang, E., Zhang, Y., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.009 · Cited by 208
“To further evaluate the mitochondrial features by independent approaches, we measured mitochondrial mass and depolarization by MitoTracker staining (Bengsch et al., 2016; Scharping et al., 2016) and found that PRODH2 knockin and lentiviral overexpressed BCMA-CAR-T cells had higher mitochondrial mass (Figure 6I) but no…”
MethodResultHomeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling
Yang, K., Blanco, D. B., Neale, G. A. M., Vogel, P., Ávila-Pacheco, J., Clish, C. B., Wu, C., Shrestha, S., Rankin, S. L., Long, L., et al. (2017) · Nature · doi:10.1038/nature23665 · Cited by 203
Role of mitochondrial alterations in human cancer progression and cancer immunity
Wang, S., Tseng, L., & Lee, H. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00956-w · Cited by 225
Activation or exhaustion of CD8+ T cells in patients with COVID-19
Rha, M., & Shin, E. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00750-4 · Cited by 201
“Exhausted CD8 T cells are known to undergo metabolic reprogramming, including decreased glycolysis and dysregulated mitochondrial energetics [95].”
BackgroundBantug, G. R., Fischer, M., Grählert, J., Balmer, M. L., Unterstab, G., Develioglu, L., Steiner, R., Zhang, L., Costa, A. S. H., Gubser, P. M., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.02.012 · Cited by 196
Gabriel, S. S., Tsui, C., Chisanga, D., Weber, F., Llano-León, M., Gubser, P. M., Bartholin, L., Souza-Fonseca-Guimarães, F., Huntington, N. D., Shi, W., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.06.007 · Cited by 200
The interplay of immunology and cachexia in infection and cancer
Baazim, H., Antonio-Herrera, L., & Bergthaler, A. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00624-w · Cited by 192
Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity
Dumauthioz, N., Tschumi, B., Wenes, M., Marti, B., Wang, H., Franco, F., Li, W., López‐Mejía, I. C., Fajas, L., Ho, P., et al. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0365-3 · Cited by 199
“Interestingly, αPD-1 treatment has been shown to enhance mitochondrial respiration in CD8 T cells in certain tumor models,(31) which is consistent with the findings that PD-1 signaling blocks PGC-1α expression and mitochondrial activity.(21) However, enforcing PGC-1α expression in CD8 T cells only tended to have an ad…”
ResultmTOR signaling at the crossroads of environmental signals and T‐cell fate decisions
Huang, H., Long, L., Zhou, P., Chapman, N. M., & Chi, H. (2020) · Immunological Reviews · doi:10.1111/imr.12845 · Cited by 193
T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma
Barsch, M., Salié, H., Schlaak, A. E., Zhang, Z., Hess, M., Mayer, L., Tauber, C., Otto-Mora, P., Ohtani, T., Nilsson, T., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.02.032 · Cited by 187
Self-citationThe function and dysfunction of memory CD 8+ T cells in tumor immunity
Reading, J. L., Gálvez‐Cancino, F., Swanton, C., Lladser, Á., Peggs, K. S., & Quezada, S. A. (2018) · Immunological Reviews · doi:10.1111/imr.12657 · Cited by 186
Metabolic adaptations of tissue-resident immune cells
Caputa, G., Castoldi, Â., & Pearce, E. J. (2019) · Nature Immunology · doi:10.1038/s41590-019-0407-0 · Cited by 179
Qiao, G., Chen, M., Mohammadpour, H., MacDonald, C. R., Bucsek, M. J., Hylander, B. L., Barbi, J. J., & Repasky, E. A. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0445 · Cited by 181
“T-cell exhaustion is associated with mitochondrial dysfunction (29-31,34-36), and our previous work shows that β-AR signaling impairs mitochondrial function (i.”
BackgroundCounteracting CAR T cell dysfunction
Poorebrahim, M., Melief, J., de Coaña, Y. P., Wickström, S. L., Arregui, A. C., & Kiessling, R. W. (2020) · Oncogene · doi:10.1038/s41388-020-01501-x · Cited by 172
“Effector T cells encountering the hostile TME or viral infections are skewed toward state with reduced effector functioning, reduced glucose uptake and glycolysis, upregulated inhibitory receptors, and increased ROS levels [89].”
BackgroundWang, B., Zhang, W., Jankovic, V., Golubov, J., Poon, P., Oswald, E. M., Gurer, C., Wei, J., Ramos, I., Wu, Q., et al. (2018) · Science Immunology · doi:10.1126/sciimmunol.aat7061 · Cited by 167
Mitochondrial activity in T cells
Desdín-Micó, G., Soto‐Heredero, G., & Mittelbrunn, M. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.10.006 · Cited by 171
Dysfunctional T cell metabolism in the tumor microenvironment
Beckermann, K. E., Dudzinski, S. O., & Rathmell, J. C. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.04.003 · Cited by 165
Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted
Tilstra, J. S., Avery, L., Menk, A. V., Gordon, R. A., Smita, S., Kane, L. P., Chikina, M., Delgoffe, G. M., & Shlomchik, M. J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120859 · Cited by 149
“Δψm is required for production of ATP, thus it has been hypothesized that suppressed Δψm may alter cellular function (40).”
Self-citationMechanisms of T-Cell Exhaustion in Pancreatic Cancer
Saka, D., Gökalp, M., Piyade, B., Çevik, N. C., Sever, E. A., Unutmaz, D., Ceyhan, G. O., Demir, İ. E., & Asimgil, H. (2020) · Cancers · doi:10.3390/cancers12082274 · Cited by 160
Metabolomics in infectious diseases and drug discovery
Tounta, V., Liu, Y., Cheyne, A., & Larrouy-Maumus, G. J. (2021) · Molecular Omics · doi:10.1039/d1mo00017a · Cited by 164
Mohanty, A., Tiwari-Pandey, R., & Pandey, N. R. (2019) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-019-00507-9 · Cited by 164
“PGC1α may therefore represent a therapeutic target for reviving exhausted CD8+ T cells in diverse settings (Bengsch et al. 2016).”
BackgroundMitochondria reactive oxygen species signaling in immune responses
Weinberg, S. E., & Chandel, N. S. (2025) · Immunity · doi:10.1016/j.immuni.2025.07.012 · Cited by 175
Gemta, L. F., Siska, P. J., Nelson, M. E., Gao, X., Liu, X., Locasale, J. W., Yagita∥, H., Slingluff, C. L., Hoehn, K. L., Rathmell, J. C., et al. (2019) · Science Immunology · doi:10.1126/sciimmunol.aap9520 · Cited by 158
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Metabolic programs define dysfunctional immune responses in severe COVID-19 patients
Thompson, E. A., Cascino, K., Ordoñez, A. A., Zhou, W., Vaghasia, A. M., Hamacher‐Brady, A., Brady, N. R., Sun, I., Wang, R., Rosenberg, A. Z., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108863 · Cited by 154
“Exhausted T cells are characterized not just by the upregulation of inhibitory molecules such as programmed cell death protein 1 (PD-1) and loss of polyfunctionality, but also by mTOR signaling in the absence of productive glycolytic function and anabolic processes 10 .”
The role of AMPK in T cell metabolism and function
Ma, E. H., Poffenberger, M. C., Wong, A., & Jones, R. G. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.04.004 · Cited by 161
TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
Slattery, K., Woods, E., Zaiatz-Bittencourt, V., Marks, S. J., Chew, S. M., Conroy, M. R., Goggin, C., Eochagáin, C. M., Kennedy, J., Lucas, S., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002044 · Cited by 153
Restoring, releasing or replacing adaptive immunity in chronic hepatitis B
Maini, M. K., & Burton, A. R. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0196-9 · Cited by 157
Liang, J., Li, H., Chen, J., He, L., Du, X., Zhou, L., Xiong, Q., Lai, X., Yang, Y., Huang, S. M., et al. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104417 · Cited by 150
Metabolic programs tailor T cell immunity in viral infection, cancer, and aging
Møller, S. H., Hsueh, P., Yu, Y.-R., Zhang, L., & Ho, P. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.003 · Cited by 154
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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