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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
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
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“PD-1 blockade in tumor models is associated with transcriptional changes in metabolic genes (Gubin et al., 2014).”
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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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“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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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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Metabolic orchestration of T lineage differentiation and function
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Genomic Circuitry Underlying Immunological Response to Pediatric Acute Respiratory Infection
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“These observations may link CD8 T cell proliferation or activation status to key metabolic processes (Bengsch et al., 2016), as well as asthma status, age, weight, and likelihood to experience more severe or prolonged consequences of IFV infection.”
Self-citationGeneral Features of Autoimmune Disease
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Age- and diet-instructed metabolic rewiring of the tumor–immune microenvironment
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P2 Receptors: Novel Disease Markers and Metabolic Checkpoints in Immune Cells
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LKB1 prevents ILC2 exhaustion to enhance antitumor immunity
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Myeloid cells meet CD8+ T cell exhaustion in cancer: What, why and how
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Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells
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“The connection between T-cell exhaustion and T-cell ageing can be explained by PD-1 repression of NRF1 cofactor Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-a) resulting in decreased expression of NRF1, and mitochondrial respiratory genes seen in T-cell ageing [69].”
BackgroundPD-1Hi CAR-T cells provide superior protection against solid tumors
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“The PD-1+ Tex cells exhibit abnormal metabolic programs in reduced glycolysis, protein glycosylation and oxidative phosphorylation (OXPHOS) (77, 78).”
BackgroundInfluentialAdvanced nanomaterials for enhanced immunotherapy via metabolic regulation
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Impact of mitochondrial dysfunction on the antitumor effects of immune cells
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CRISPR Screens to Identify Regulators of Tumor Immunity
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Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment
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“In addition, exhausted CD8+ T cells have altered metabolic and bioenergetic pathways, and downregulated translational abilities [18,19].”
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Industry 'road tests' new wave of immune checkpoints
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“Furthermore, elevated Akt signaling in TILs potently represses the transcriptional co-activator PGC-1α, a key regulator of mitochondrial biogenesis [162].”
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“PD-1 activation alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation (29).”
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“Notably, the change in GLUT3 level after ICI treatment was different between responders and non-responders in myeloid cells, instead of CD8 T-cells (Figure 4D).”
ResultInfluentialWu, K., Han, N., Mao, Y., & Li, Y. (2023) · BMC Oral Health · doi:10.1186/s12903-023-03043-6 · Cited by 12
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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