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.
“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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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× · see citing works
“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× · see citing works
“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 3,960 · cited 1× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
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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× · see citing works
“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× · see citing works
“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× · see citing works
“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).”
BackgroundMitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development
van der Windt, G. J. W., Everts, B., Chang, C.-H., Curtis, J. D., Freitas, T. C., Amiel, E., Pearce, E. J., & Pearce, E. L. (2012) · Immunity · doi:10.1016/j.immuni.2011.12.007 · Cited by 1,540 · cited 2× · see citing works
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BackgroundMethodPhosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ho, P.-C., Bihuniak, J. D., Macintyre, A. N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.-C., Cui, G., Micevic, G., Perales, J. C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.012 · Cited by 1,462 · cited 4× · see citing works
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BackgroundInfluentialMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S., 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.2007.11.006 · Cited by 1,355 · see citing works
Self-citationPatsoukis, N., Bardhan, K., Chatterjee, P., Sari, D., Liu, B., Bell, L. N., Karoly, E. D., Freeman, G. J., Petkova, V., Seth, P., et al. (2015) · Nature Communications · doi:10.1038/ncomms7692 · Cited by 1,210 · cited 5× · see citing works
“In vitro, engaging PD-1 or CTLA-4 on activated T cells reduces Akt and mTOR signaling, and suppresses glycolysis (Parry et al., 2005; Patsoukis et al., 2015).”
BackgroundResultInfluentialT cell metabolism drives immunity
Buck, M. D., O’Sullivan, D., & Pearce, E. L. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151159 · Cited by 1,190 · cited 3× · see citing works
“Teff cells generated during acute infections switch to anabolic metabolism dominated by aerobic glycolysis (Buck et al., 2015).”
BackgroundInfluentialYokosuka, T., Takamatsu, M., Kobayashi-Imanishi, W., Hashimoto-Tane, A., Azuma, M., & Saito, T. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112741 · Cited by 1,161 · cited 1× · see citing works
“Engagement of PD-1 by its ligand PD-L1 results 358 Immunity 45, 358–373, August 16, 2016 ª 2016 Elsevier Inc. in the formation of microclusters with the TCR (Yokosuka et al., 2012) and PD-1 inhibits proximal signaling molecules after TCR engagement (Sheppard et al., 2004).”
BackgroundOkazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S., & Honjo, T. (2013) · Nature Immunology · doi:10.1038/ni.2762 · Cited by 915 · cited 1× · see citing works
“As a result, PD-1 can function asa rheostat to tuneTCRsignaling in tissuesduring infections (Honda et al., 2014;Okazaki et al., 2013).”
BackgroundProgenitor and Terminal Subsets of CD8 + T Cells Cooperate to Contain Chronic Viral Infection
Paley, M., Kroy, D. C., Odorizzi, P. M., Johnnidis, J. B., Dolfi, D. V., Barnett, B. E., Bikoff, E. K., Robertson, E. J., Lauer, G. M., Reiner, S. L., et al. (2012) · Science · doi:10.1126/science.1229620 · Cited by 903 · cited 4× · see citing works
“Whereas both subsets are required for control of chronic infection, the PD-1Int subset functions as a progenitor pool giving rise to terminally differentiated PD-1Hi cells (Paley et al., 2012).”
BackgroundInfluentialSelf-citationOkazaki, T., Maeda, A., Nishimura, H., Kurosaki, T., & Honjo, T. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.231486598 · Cited by 849 · cited 1× · see citing works
“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).”
BackgroundRegulation of Immune Responses by mTOR
Powell, J. D., Pollizzi, K. N., Heikamp, E. B., & Horton, M. R. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075024 · Cited by 836 · cited 1× · see citing works
“Despite the advantages of rapamycin treatment for the metabolic phenotype of early Tex cells, its use is unlikely to be of overall benefit in a therapeutic setting, given its immunosuppressive effects (Powell et al., 2012).”
BackgroundSheppard, K.-A., Fitz, L. J., Lee, J. M., Benander, C., George, J. A., Wooters, J., Qiu, Y., Jussif, J. M., Carter, L. L., Wood, C. R., et al. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.07.083 · Cited by 791 · cited 1× · see citing works
“Engagement of PD-1 by its ligand PD-L1 results 358 Immunity 45, 358–373, August 16, 2016 ª 2016 Elsevier Inc. in the formation of microclusters with the TCR (Yokosuka et al., 2012) and PD-1 inhibits proximal signaling molecules after TCR engagement (Sheppard et al., 2004).”
BackgroundO’Sullivan, D., van der Windt, G. J. W., Huang, S. C.-C., Curtis, J. D., Chang, C.-H., Buck, M. D., Qiu, J., Smith, A. M., Lam, W. Y., DiPlato, L. M., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.005 · Cited by 790 · see citing works
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“PGC-1a is a key transcriptional regulator of genes controlling energy metabolism and mitochondrial biogenesis (Austin and St-Pierre, 2012).”
BackgroundSelective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade
Blackburn, S. D., Shin, H., Freeman, G. J., & Wherry, E. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801497105 · Cited by 575 · cited 2× · see citing works
“Targeted blockade of PD-1 is effective in improving T cell function and reducing viral replication, mainly by reinvigorating the PD-1Int Tex cell subset (Blackburn et al., 2008).”
BackgroundSelf-citationDoering, T. A., Crawford, A., Angelosanto, J., Paley, M., Ziegler, C. G. K., & Wherry, E. J. (2012) · Immunity · doi:10.1016/j.immuni.2012.08.021 · Cited by 542 · cited 2× · see citing works
“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-citationMacIver, N. J., Jacobs, S. R., Wieman, H. L., Wofford, J. A., Coloff, J. L., & Rathmell, J. C. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0108024 · Cited by 501 · cited 1× · see citing works
“This early peak in glucose uptake is consistent with other data on in vitro activated Teff-like cells (Chang et al., 2013; Maciver et al., 2008; Patsoukis et al., 2015), but the decline in glucose uptake indicates a dynamic regulation in vivo that is distinct from short-term in vitro culture.”
ResultMolecular and Transcriptional Basis of CD4+ T Cell Dysfunction during Chronic Infection
Crawford, A., Angelosanto, J., Kao, C., Doering, T. A., Odorizzi, P. M., Barnett, B. E., & Wherry, E. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.01.005 · Cited by 498 · cited 2× · see citing works
“…relatively few differences in LCMV-specific CD8+ T cells responding to acutely cleared Arm versus the chronic clone 13 strains of LCMV in early infection (day 6 and day 8 post infection [p.i.]) compared to later time points (day 30+) (Figure 1A) (Crawford et al., 2014; Doering et al., 2012).”
BackgroundSelf-citationGenetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells
Odorizzi, P. M., Pauken, K. E., Paley, M., Sharpe, A. H., & Wherry, E. J. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20142237 · Cited by 470 · cited 12× · see citing works
“Mice, Infections, Adoptive Transfer, and Treatments Pdcd1"/" (Keir et al., 2007), LCMV GP33-specific TCR transgenic ‘‘P14,’’ Pdcd1+/+ P14 (Odorizzi et al., 2015), and C57BL/6 mice (Charles River) were housed at the University of Pennsylvania (Philadelphia, PA) and treated in accordance with…”
BackgroundMethodResultInfluentialSelf-citationStaron, M. M., Gray, S. M., Marshall, H. D., Parish, I. A., Chen, J. H., Perry, C. J., Cui, G., Li, M. O., & Kaech, S. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.013 · Cited by 384 · cited 5× · see citing works
“In vivo, a feedback loopbetweenPD-1and the transcription factor Foxo1 exists that desensitizes antigen-induced signaling via the Akt and mTOR pathway, fostering survival of more terminally differentiatedPD-1HiEomesHi Tex cells (Staron et al., 2014).”
BackgroundResultInfluentialKurachi, M., Barnitz, R. A., Yosef, N., Odorizzi, P. M., DiIorio, M. A., Lemieux, M. E., Yates, K. B., Godec, J., Klatt, M. G., Regev, A., et al. (2014) · Nature Immunology · doi:10.1038/ni.2834 · Cited by 384 · cited 1× · see citing works
“RV-transduced P14 cells were adoptively transferred into recipient infected mice, as described (Kurachi et al., 2014).”
MethodSelf-citationAngelosanto, J., Blackburn, S. D., Crawford, A., & Wherry, E. J. (2012) · Journal of Virology · doi:10.1128/jvi.00889-12 · Cited by 285 · cited 2× · see citing works
“Early, but not established Tex cells, have developmental plasticity and could develop into functional Tmem cells if isolated during the first week, but not later in infection (Angelosanto et al., 2012).”
BackgroundSelf-citationT cells and reactive oxygen species
Belikov, A. V., Schraven, B., & Simeoni, L. (2015) · Journal of Biomedical Science · doi:10.1186/s12929-015-0194-3 · Cited by 264 · cited 1× · see citing works
“Accumulation of ROS might inflict damage to cellular proteins and DNA, potentially leading to apoptosis (Belikov et al., 2015).”
BackgroundPD-1 Regulates Self-Reactive CD8+ T Cell Responses to Antigen in Lymph Nodes and Tissues
Keir, M. E., Freeman, G. J., & Sharpe, A. H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.8.5064 · Cited by 243 · cited 3× · see citing works
“Mice, Infections, Adoptive Transfer, and Treatments Pdcd1"/" (Keir et al., 2007), LCMV GP33-specific TCR transgenic ‘‘P14,’’ Pdcd1+/+ P14 (Odorizzi et al., 2015), and C57BL/6 mice (Charles River) were housed at the University of Pennsylvania (Philadelphia, PA) and treated in accordance with protocols approved by the I…”
MethodHonda, T., Egen, J. G., Lämmermann, T., Kastenmüller, W., Torabi‐Parizi, P., & Germain, R. N. (2014) · Immunity · doi:10.1016/j.immuni.2013.11.017 · Cited by 239 · cited 1× · see citing works
“As a result, PD-1 can function asa rheostat to tuneTCRsignaling in tissuesduring infections (Honda et al., 2014;Okazaki et al., 2013).”
BackgroundProgrammed death 1 protects from fatal circulatory failure during systemic virus infection of mice
Frebel, H., Nindl, V., Schuepbach, R. A., Braunschweiler, T., Richter, K., Vogel, J., Wagner, C. A., Loffing‐Cueni, D., Kurrer, M. O., Ludewig, B., et al. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20121015 · Cited by 210 · cited 2× · see citing works
“In this model, Pdcd1"/" P14 cells preferentially expanded at d8 p.i. consistent with previous studies (Frebel et al., 2012; Odorizzi et al., 2015).”
BackgroundResultTrans-mitochondrial coordination of cristae at regulated membrane junctions
Picard, M., McManus, M. J., Csordás, G., Várnai, P., Dorn II, G. W., Williams, D., Hajnóczky, G., & Wallace, D. C. (2015) · Nature Communications · doi:10.1038/ncomms7259 · Cited by 166 · cited 1× · see citing works
“Processing and staining was performed as described (Picard et al., 2015).”
MethodBrooks, D. G. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26856 · Cited by 141 · cited 1× · see citing works
“T cell commitment to exhaustion is thought to occur progressively over time (Angelosanto et al., 2012; Brooks et al., 2006; Crawford et al., 2014).”
BackgroundPD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A
Patsoukis, N., Sari, D., & Boussiotis, V. A. (2012) · Cell Cycle · doi:10.4161/cc.22135 · Cited by 137 · cited 1× · see citing works
“In addition, PD-1 ligation attenuates PI3K and Akt signaling inhibiting cell cycle at the G1 stage (Patsoukis et al., 2012).”
BackgroundAntitumour immunity gets a boost
Wolchok, J. D., & Chan, T. A.-T. (2014) · Nature · doi:10.1038/515496a · Cited by 108 · cited 1× · see citing works
“Inhibitory receptor blockade targeting immune checkpoints is also transforming human cancer therapy with impressive responses in multiple types of malignancies presumably due to reversal of T cell exhaustion (Wolchok and Chan, 2014).”
BackgroundCTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms.
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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
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“these metabolic defects, including PGC1α (106, 107) and Foxo1 (108) pathways.”
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Sharpe, A. H., & Pauken, K. E. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.108 · Cited by 1,977 · see citing works
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“Two CD4 effector T cell subsets were identified in the TME, and both display an activated phenotype but differ in their expression of key markers including PD-1 and TBET (Figure 1G).”
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“…shown that PD-1 contributes to these early glycolytic and mitochondrial changes, as PD-1 deficient T cells do not undergo these metabolic changes in the murine LCMV model, and as the key metabolic regulator PPAR-gamma coactivator 1a (PGC-1a) is repressed by PD-1 triggering (Bengsch et al., 2016).”
BackgroundMetabolic Instruction of Immunity
Buck, M. D., Sowell, R., Kaech, S. M., & Pearce, E. L. (2017) · Cell · doi:10.1016/j.cell.2017.04.004 · Cited by 1,232 · see citing works
“PD-1 not only suppresses TCR, PI3K and mTOR signaling in T cells, but also dampens glycolysis and promotes fatty acid oxidation (FAO) – features that may enhance the accumulation of suppressive regulatory CD4 T (Treg) cells in tumors (Bengsch et al., 2016; Parry et al., 2005; Patsoukis et al., 2015).”
Mitochondria are the powerhouses of immunity
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“During chronic viral infection, PGC1α overexpression promotes viral clearance by overcoming PD-1-mediated suppression of mitochondrial metabolism, facilitating the glycolytic reengagement needed for Te cell function (93).”
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“Interestingly, one mechanism of thede-activatingeffect ofPD-1onTcell activationcould involve PD-1-mediated suppression of glycolysis in the T cells themselves, as has been shown recently for CD8+ T cells (Bengsch et al., 2016).”
CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions
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CD8+ T cell metabolism in infection and cancer
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Metabolic barriers to cancer immunotherapy
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Self-citationDisturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
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Navigating CAR-T cells through the solid-tumour microenvironment
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Immune checkpoints and their inhibition in cancer and infectious diseases
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Precursor exhausted T cells: key to successful immunotherapy?
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Metabolic and epigenetic regulation of T-cell exhaustion
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CD8+ T cells in the cancer-immunity cycle
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Resistance Mechanisms to Anti-PD Cancer Immunotherapy
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Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity
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T‐cell exhaustion in HIV infection
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The spectrum of T cell metabolism in health and disease
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Successful and Maladaptive T Cell Aging
Goronzy, J. J., & Weyand, C. M. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.010 · Cited by 362 · see citing works
“Repression of PGC1a, an important cofactor of NRF1 activity, is an early event in T cell exhaustion, indicating a mechanistic overlap between T cell aging and exhaustion (Bengsch et al., 2016).”
BackgroundBaessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420 · see citing works
Siska, P. J., Beckermann, K. E., Mason, F. M., Andrejeva, G., Greenplate, A. R., Sendor, A. B., Chiang, Y.-C. J., Corona, A. L., Gemta, L. F., Vincent, B. G., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.93411 · Cited by 389 · see citing works
An evolutionary perspective on immunometabolism
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Lessons learned from the blockade of immune checkpoints in cancer immunotherapy
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Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment
Zhao, Y., Shao, Q., & Peng, G. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0344-8 · Cited by 382 · see citing works
“Both anti-PD-1 antibody immunotherapy and PGC1α overexpression can rescue T-cell metabolism and improve the metabolic fitness of exhausted T cells in experimental tumor models.(107,109,111,115) Furthermore, enhanced antitumor immunity mediated by 4-1BB costimulation is due to the promotion of the mitochondrial capacit…”
BackgroundCXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer
Gu-Trantien, C., Migliori, E., Buisseret, L., de Wind, A., Brohée, S., Garaud, S., Noël, G., Dang Chi, V. L., Lodewyckx, J.-N., Naveaux, C., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.91487 · Cited by 368 · see citing works
PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux
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Modulating Glycolysis to Improve Cancer Therapy
Chelakkot, C., Chelakkot, V. S., Shin, Y. K., & Song, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032606 · Cited by 378 · see citing works
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“PD-1 inhibits mTOR pathway activation and suppresses glycolysis in T cells (42).”
BackgroundSpatiotemporal Co-Dependency between Macrophages and Exhausted CD8 + T Cells in Cancer
Kersten, K., Hu, K. H., Combes, A. J., Samad, B., Harwin, T., Ray, A., Rao, A. A., Cai, E., Marchuk, K., Artichoker, J., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2022.05.004 · Cited by 348 · see citing works
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“They reported that PD-1 signals inhibit the expression of keymetabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and interestingly overexpression of PGC1α corrected some metabolic alterations in developing exhausted T cells and improved effector function (120).”
BackgroundCancer Epigenetics, Tumor Immunity, and Immunotherapy
Cao, J., & Yan, Q. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.02.003 · Cited by 298 · see citing works
Acetate Promotes T Cell Effector Function during Glucose Restriction
Qiu, J., Villa, M., Sanin, D. E., Buck, M. D., O’Sullivan, D., Ching, R., Matsushita, M., Grzes, K. M., Winkler, F., Chang, C.-H., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.022 · Cited by 342 · see citing works
“Cell R from a lack of available substrate or a lack of ability to acquire substrate, during their response to persistent virus infection that may potentially lead to T cell exhaustion and/or hyporesponsiveness (Bengsch et al., 2016; Wedemeyer et al., 2002).”
BackgroundSelf-citationFisicaro, P., Barili, V., Montanini, B., Acerbi, G., Ferracin, M., Guerrieri, F., Salerno, D., Boni, C., Massari, M., Cavallo, M. C., et al. (2017) · Nature Medicine · doi:10.1038/nm.4275 · Cited by 344 · see citing works
The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy
Lim, A. R., Rathmell, W. K., & Rathmell, J. C. (2020) · eLife · doi:10.7554/elife.55185 · Cited by 330 · see citing works
“…receptorg coactivator (PGC-1a) increased glucose uptake and decreased mitochondrial mass and polarization, and it enhances the function of exhausted T cells in both a lymphocytic choriomeningitis virus (LCMV) infection (Bengsch et al., 2016) and in a B16 melanoma model (Scharping et al., 2016).”
BackgroundWu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42634-3 · Cited by 334 · see citing works
Immunometabolic Interplay in the Tumor Microenvironment
Kaymak, I., Williams, K. S., Cantor, J. R., & Jones, R. G. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.09.004 · Cited by 332 · see citing works
“Tex cells are associated with metabolic insufficiency that may be driven in part by the activation of one (or more) checkpoint inhibitor receptors, such as PD-1, LAG3, or CTLA-4 (Bengsch et al., 2016; Previte et al., 2019).”
BackgroundBi, J., & Tian, Z. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00760 · Cited by 327 · see citing works
Kurachi, M. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00744-5 · Cited by 317 · see citing works
Self-citationSingle-cell metabolic profiling of human cytotoxic T cells
Hartmann, F. J., Mrdjen, D., McCaffrey, E., Glass, D. R., Greenwald, N. F., Bharadwaj, A., Khair, Z., Verberk, S. G. S., Baranski, A., Baskar, R., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0651-8 · Cited by 310 · see citing works
Metabolic adaptation of lymphocytes in immunity and disease
Chapman, N. M., & Chi, H.-B. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.012 · Cited by 263 · see citing works
“In established chronic LCMV infection, the metabolic alterations, especially defective mitochondrial fitness, occur exclusively in terminal Tex cells, and antagonism of PD-1 signaling rectifies the dysfunctional metabolic profiles of early Tex cells (Bengsch et al., 2016; Gabriel et al., 2021).”
BackgroundInfluentialLinoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity
Lauson, C. B. N., Tiberti, S., Corsetto, P. A., Conte, F., Tyagi, P., Machwirth, M., Ebert, S., Loffreda, A., Scheller, L., Sheta, D., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.02.013 · Cited by 294 · see citing works
Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity
Phan, A. T., Goldrath, A. W., & Glass, C. K. (2017) · Immunity · doi:10.1016/j.immuni.2017.04.016 · Cited by 291 · see citing works
CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities
Fonkoua, L. A. K., Sirpilla, O. L., Sakemura, R. L., Siegler, E. L., & Kenderian, S. S. (2022) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2022.03.009 · Cited by 299 · see citing works
“This stress results in transcriptional and enzymatic signature changes that characterize the dysfunctionally exhausted state of CAR T cells and associated compromised antitumor immunity.(51,52)”
BackgroundReprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy
Liu, X., Hartman, C. L., Li, L., Albert, C. J., Si, F., Gao, A., Huang, L. J., Zhao, Y., Lin, W., Hsueh, E. C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz6314 · Cited by 278 · see citing works
The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance
Schönrich, G., & Raftery, M. J. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00207 · Cited by 272 · see citing works
“Intriguingly, PD-1-regulated changes in several metabolic pathways occur at the very beginning of Tex cell development underlining the importance of these metabolic processes in the execution of the Tex program (Bengsch et al., 2016; Schurich et al., 2016; McKinney and Smith, 2018).”
BackgroundCellular metabolism regulates the differentiation and function of T-cell subsets
Ma, S., Ming, Y., Wu, J., & Cui, G. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01148-8 · Cited by 255 · see citing works
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 239 · see citing works
“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 233 · see citing works
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 232 · see citing works
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 · see citing works
“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 · see citing works
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“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 199 · see citing works
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 208 · see citing works
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 193 · see citing works
“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 191 · see citing works
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 193 · see citing works
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 188 · see citing works
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., Lluis Fajas, A., Ho, P., et al. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0365-3 · Cited by 191 · see citing works
“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 · see citing works
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 · see citing works
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 182 · see citing works
Metabolic adaptations of tissue-resident immune cells
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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 179 · see citing works
“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., Cid-Arregui, Á., & Kiessling, R. W. (2020) · Oncogene · doi:10.1038/s41388-020-01501-x · Cited by 169 · see citing works
“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 · see citing works
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 162 · see citing works
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 159 · see citing works
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 · see citing works
“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 154 · see citing works
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 157 · see citing works
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“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 166 · see citing works
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 155 · see citing works
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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 152 · see citing works
“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 154 · see citing works
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 · see citing works
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 152 · see citing works
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 · see citing works
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 148 · see citing works
- 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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