Blockade of PD‐1 or p38 MAP kinase signaling enhances senescent human CD8+ T‐cell proliferation by distinct pathways
Open accessAbstract
Immune enhancement is desirable in situations where decreased immunity results in increased morbidity. We investigated whether blocking the surface inhibitory receptor PD‐1 and/or p38 MAP kinase could enhance the proliferation of the effector memory CD8+ T‐cell subset that re‐expresses CD45RA (EMRA) and exhibits characteristics of senescence, which include decreased proliferation and telomerase activity but increased expression of the DNA damage response related protein γH2AX. Blocking of both PD‐1 and p38 MAPK signaling in these cells enhanced proliferation and the increase was additive when both pathways were inhibited simultaneously in both young and old human subjects. In contrast, telomerase activity in EMRA CD8+ T cells was only enhanced by blocking the p38 but not the PD‐1 signaling pathway, further indicating that nonoverlapping signaling pathways were involved. Although blocking p38 MAPK inhibits TNF‐α secretion in the EMRA population, this decrease was counteracted by the simultaneous inhibition of PD‐1 signaling in these cells. Therefore, end‐stage characteristics of EMRA CD8+ T cells are stringently controlled by distinct and reversible cell signaling events. In addition, the inhibition of PD‐1 and p38 signaling pathways together may enable the enhancement of proliferation of EMRA CD8+ T cells without compromising their capacity for cytokine secretion.
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Unlike cellular senescence in a strict sense, these functional deficits are reversed by inhibiting p38.
“Unlike cellular senescence in a strict sense, these functional deficits are reversed by inhibiting p38”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Henson et al., 2015
Proliferation of TEMRAs is in part restored by PD-1 blockade, yet without improving telomerase activity.
“Proliferation of TEMRAs is in part restored by PD-1 blockade, yet without improving telomerase activity”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Henson et al., 2015
PD-1 expression is low and T-bet expression is high in TEMRAs.
“PD-1 expression is low and T-bet expression is high in TEMRAs”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Henson et al., 2015
Within primary human T cells, both CD4+ and CD8+ populations contain a subset of poorly proliferative cells with characteristics very similar to senescent fibroblasts.
“Within primary human T cells, in both CD4 + [23, 28, 29] and CD8 + [25, 30] populations, there is a subset of poorly proliferative cells that exhibit characteristics that are very similar to senescent fibroblasts (Fig. 1).”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
Senescent-like T cells can be identified by surface marker expression CD27-, CD28-, CD45RA+, KLRG1+, CD57+, which are characteristics of highly differentiated T cells.
“These cells can be identified by surface marker expression (CD27 - ,CD28 - , CD45RA + , KLRG1 + , CD57 + ) that are all characteristics of highly differentiated T cells [23, 28, 30, 31].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
Highly differentiated CD27-CD28- T cells that re-express CD45RA have multiple characteristics of senescence including loss of telomerase activity, DNA damage, high levels of reactive oxygen species and the lowest proliferative capacity.
“The highly differentiated CD27 - CD28 - population of T cells can be further divided and the cells that re-express CD45RA within this subset have multiple characteristics of senescence including loss of telomerase activity, DNA damage, high levels of reactive oxygen species (ROS) and the lowest proliferative capacity [25, 30].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
Using small molecule inhibitors or specific inhibitory shRNA, p38 inhibition reconstituted proliferation and telomerase activity in T cells after activation.
“Using small molecule inhibitors [23, 30] or specific inhibitory shRNA [24] it was found that p38 inhibition reconstituted proliferation and also telomerase activity in T cells after activation.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
CD45RA re-expressing senescent T cells do not have critically short telomeres, suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased ROS production.
“Intriguingly, the CD45RA re-expressing senesecent T cells do not have critically short telomeres suggesting that senescence in these cell may be induced by other mechanisms including DNA damage by increased ROS production [25, 30].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
Compared to less differentiated populations, senescent T cells secrete high levels of inflammatory cytokines IFN-gamma and TNF-alpha after short term activation.
“In comparison to less differentiated populations, senescent T cells also secrete high levels of inflammatory cytokines such IFN and TNF after short term activation [28, 30, 50]”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
Based on in vitro data, blocking agents to p38 could be used in vivo to enhance certain T cell functions.
“One target for reversing senescence in T cells would be the p38 MAP kinase pathway and based on data that has been obtained in vitro , blocking agents to p38 could be used in vivo to enhance certain T cell functions [23-25, 30] .”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
The pathway involved in PD1 engagement in senescent human T cells is different from that induced by p38 MAP signalling, as there is additive enhancement of proliferation when both PD1 and p38 pathways are blocked simultaneously.
“The pathway involved in PD1 engagement in senescent human T cells is different for that induced by p38 MAP signalling as there is an additive enhancement of proliferation when both PD1 and p38 pathways are blocked simultaneously [30].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [30]
p38 MAPK blockade could reverse CD8+ T-cell senescence via an mTOR-independent autophagy pathway.
“The fundamental metabolic requirements of senescent primary human CD8+ T cells were elucidated in a recent study, where it was shown that p38 MAPK blockade could reverse CD8+ T-cell senescence via a mTOR-independent pathway, i.e., via the autophagy pathway [92].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [92]
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“Only 28% of the studies did not describe whether the measurement was done on frozen or fresh cells (15, 22, 23, 26, 28–31, 49, 50); 33% of the articles did not report the number of cells used in each experiment (15, 17, 18, 20, 22, 24–26, 28, 31, 35, 36), while only 31% clearly described the antibodies with fluorochro…”
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ResultKnaus, H. A., Berglund, S., Hackl, H., Blackford, A. L., Zeidner, J. F., Montiel-Esparza, R., Mukhopadhyay, R., Vanura, K., Blazar, B. R., Karp, J. E., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.120974 · Cited by 216 · see citing works
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“Blocking signaling by p38 and PD‐1 can enhance cell proliferation (Henson et al., 2015).”
BackgroundSuen, H., Brown, R. D., Yang, S. S., Weatherburn, C., Ho, P. J., Woodland, N., Nassif, N. T., Barbaro, P., Bryant, C. E., Hart, D. N. J., et al. (2016) · Leukemia · doi:10.1038/leu.2016.84 · Cited by 201 · see citing works
Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly
Pereira, B. I., Xu, X., & Akbar, A. N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.583019 · Cited by 182 · see citing works
“As the expression of inhibitory receptors on T cells has been shown to increase with age and differentiation (37, 167) the selective blockade of inhibitory receptors known to regulate T cell activity could be explored as means of boosting cellular responses in the elderly prior to or during vaccination.”
BackgroundSelf-citationSenescent T cells: a potential biomarker and target for cancer therapy
Zhang, J., He, T., Xue, L., & Guo, H. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103409 · Cited by 171 · see citing works
“The senescence-associated secretory phenotype (SASP) [11,13,15-19] and metabolic changes (discussed further in the following sections) [13,17,20,21] are also present in senescent T cells.”
BackgroundInfluentialMitochondrial mass governs the extent of human T cell senescence
Callender, L. A., Carroll, E. C., Bober, E., Akbar, A. N., Solito, E., & Henson, S. M. (2019) · Aging Cell · doi:10.1111/acel.13067 · Cited by 167 · see citing works
Self-citationFrasca, D., Diaz, A., Romero, M., & Blomberg, B. B. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2016.12.001 · Cited by 160 · see citing works
Ferrara, R., Naigeon, M., Auclin, É., Duchemann, B., Cassard, L., Jouniaux, J.-M., Boselli, L., Grivel, J., Desnoyer, A., Mezquita, L., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1420 · Cited by 163 · see citing works
“In vitro experiments showed that blocking PD-1 had no effect on proliferation or functionality of circulating human TEMRA (CD45RAþ CD27 ) T cells, while both were increased by blocking senescence (13), supporting the hypothesis that senescence and exhaustion may involve distinct pathways and that reversing senescence…”
BackgroundInfluentialMulti-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies
Gurusamy, D., Henning, A. N., Yamamoto, T. N., Yu, Z., Zacharakis, N., Krishna, S., Kishton, R. J., Vodnala, S. K., Eidizadeh, A., Jia, L., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.05.004 · Cited by 159 · see citing works
Immunotherapy comes of age: Immune aging & checkpoint inhibitors
Elias, R., Karantanos, T., Sira, E., & Hartshorn, K. L. (2017) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2017.02.001 · Cited by 133 · see citing works
Type 2 diabetes is associated with the accumulation of senescent T cells
Lau, E. Y. M., Carroll, E. C., Callender, L. A., Hood, G., Berryman, V., Pattrick, M., Finer, S., Hitman, G. A., Ackland, G. L., & Henson, S. M. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13344 · Cited by 116 · see citing works
Self-citationBasic science and pathogenesis of ageing with HIV
Lagathu, C., Cossarizza, A., Béréziat, V., Nasi, M., Capeau, J., & Pinti, M. (2017) · AIDS · doi:10.1097/qad.0000000000001441 · Cited by 108 · see citing works
“Many TEMRA cells are anergic, with senescent, cytotoxic, and inflammatory features [148,149].”
BackgroundThe role of senescent T cells in immunopathology
Covre, L. P., De Maeyer, R. P. H., Gomes, D. C. O., & Akbar, A. N. (2020) · Aging Cell · doi:10.1111/acel.13272 · Cited by 93 · see citing works
“Recent studies show that these cells also harbour DNA damage, short telomeres, low telomerase activity and engage signalling pathways associated with cellular senescence (Callender et al., 2018; Henson et al., 2014; Lanna et al., 2014).”
InfluentialSelf-citationArasanz, H., Zuazo, M., Bocanegra, A., Gato, M., Martínez-Aguillo, M., Morilla, I., Fernández, G., Hernández, B., López, P., Alberdi, N., et al. (2020) · Cancers · doi:10.3390/cancers12020344 · Cited by 89 · see citing works
Frasca, D. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2017.07.002 · Cited by 82 · see citing works
“Similar to LM B cells, terminally-differentiated CD4+ T cells (Henson et al., 2014; Henson et al., 2015; Lanna et al., 2014) show spontaneous activation of AMPKwhich leads to the recruitment of p38MAPK to the scaffold protein TAB1 and consequent p38MAPK phosphorylation, resulting in inhibition of…”
BackgroundResultT Cell Immunosenescence in Aging, Obesity, and Cardiovascular Disease
Shirakawa, K., & Sano, M. (2021) · Cells · doi:10.3390/cells10092435 · Cited by 87 · see citing works
The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease
Weyand, C. M., Berry, G. J., & Goronzy, J. J. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ma0717-283 · Cited by 83 · see citing works
Human T Cell Memory: A Dynamic View
Macallan, D. C., Borghans, J. A. M., & Asquith, B. (2017) · Vaccines · doi:10.3390/vaccines5010005 · Cited by 78 · see citing works
“In the elderly, for example, it appears that P38 may be a crucial contributor to CD8 T cell senescence and that its effects may be reversible [53].”
BackgroundImmune Aging and Immunotherapy in Cancer
Kaiser, M., Semeraro, M. D., Herrmann, M., Absenger, G., Gerger, A., & Renner, W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137016 · Cited by 78 · see citing works
Kim, C. M., Lee, J. B., Shin, S. J., Ahn, J. B., Lee, M., & Kim, H. S. (2022) · ESMO Open · doi:10.1016/j.esmoop.2022.100577 · Cited by 75 · see citing works
Signal transduction changes in CD4 + and CD8 + T cell subpopulations with aging
Page, A. Y. L., Dupuis, G., Larbi, A., Witkowski, J. M., & Fülöp, T. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.01.005 · Cited by 65 · see citing works
“Of interest, modulation of the inhibitory activity of the PD-1 co-receptor that acts through protein phosphatases such as SHP1 successfully increased the functions of CD8 T cells of elderly donors (Henson et al., 2015).”
InfluentialSenescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword
Battram, A. M., Bachiller, M., & Martín-Antonio, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124346 · Cited by 63 · see citing works
Senescent T cells: Beneficial and detrimental roles
Laphanuwat, P., Gomes, D. C. O., & Akbar, A. N. (2023) · Immunological Reviews · doi:10.1111/imr.13206 · Cited by 61 · see citing works
Self-citationKnowns and Unknowns about CAR-T Cell Dysfunction
Titov, A., Kaminskiy, Y., Ganeeva, I., Zmievskaya, E., Valiullina, A., Rakhmatullina, A., Petukhov, A., Рифкатовна, М. Р., Rizvanov, A. A., & Bulatov, E. (2022) · Cancers · doi:10.3390/cancers14041078 · Cited by 56 · see citing works
The effect of metformin on senescence of T lymphocytes
Yang, J. H., Liu, H.-C., Zhang, J., Zou, J., Zhang, X., Chen, W., Gu, Y., & Hong, H. Y. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00394-0 · Cited by 54 · see citing works
“Senescent T cells have high levels of intracellular granules and secrete inflammatory cytokines, such as IFN-γ and TNF-α, after short-term activation [6, 7].”
BackgroundIntracellular signalling pathways: targets to reverse immunosenescence
Fülöp, T., Witkowski, J. M., Page, A. Y. L., Fortin, C. F., Pawelec, G., & Larbi, A. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12836 · Cited by 53 · see citing works
Reversing the immune ageing clock: lifestyle modifications and pharmacological interventions
Duggal, N. A. (2018) · Biogerontology · doi:10.1007/s10522-018-9771-7 · Cited by 53 · see citing works
“…detrimental. p38 MAP kinase inhibition T cells with senescent characteristics increase with age and exhibit constitutive p38 MAPK activation (Hen- son et al. 2015), with recent data revealing that this is due to formation of a complex between MAP kinases and the sestrin family of proteins…”
BackgroundThe clock is ticking: the impact of ageing on T cell metabolism
Quinn, K. M., Palchaudhuri, R., Palmer, C. S., & Gruta, N. L. L. (2019) · Clinical & Translational Immunology · doi:10.1002/cti2.1091 · Cited by 51 · see citing works
Guan, L., Crasta, K., & Maier, A. B. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101634 · Cited by 53 · see citing works
Are immunosenescent T cells really senescent?
Slaets, H., Veeningen, N., de Keizer, P. L. J., Hellings, N., & Hendrix, S. (2024) · Aging Cell · doi:10.1111/acel.14300 · Cited by 50 · see citing works
“In addition, yH2Ax is upregulated in TEMRA cells and CD28null T cells (Di Mitri et al., 2011; Henson et al., 2015; Lanna et al., 2014).”
BackgroundThe life cycle of a T cell after vaccination – where does immune ageing strike?
Kim, C., Fang, F., Weyand, C. M., & Goronzy, J. J. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12829 · Cited by 50 · see citing works
The role of the CD8+ T cell compartment in ageing and neurodegenerative disorders
Terrabuio, E., Zenaro, E., & Constantin, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1233870 · Cited by 48 · see citing works
Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging
Gustafson, C. E., Qi, Q., Hutter-Saunders, J. A. L., Gupta, S., Jadhav, R. R., Newell, E. W., Maecker, H. T., Weyand, C. M., & Goronzy, J. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00692 · Cited by 47 · see citing works
“However, unlike cellular senescence in a strict sense, these functional deficits are reversed by inhibiting p38 (44, 45).”
BackgroundThe P2X7 Receptor in Tumor Immunity
Grassi, F., & Conti, B. D. P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.694831 · Cited by 42 · see citing works
“A vast repertoire of pharmacological tools has been developed to define P2 receptor functions and to be possibly used in clinical trials for various pathological conditions (Jacobson and Muller, 2016).”
BackgroundCovre, L. P., Martins, R. F., Devine, O., Chambers, E. S., Vukmanovic‐Stejic, M., Silva, J. A., Dietze, R., Rodrigues, R. R., Guedes, H. L. D. M., Falqueto, A., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03001 · Cited by 46 · see citing works
“However, in the present and previous studies (31), we have used KLRG1 expression in conjunction with other markers to define senescent T cells.”
ResultSelf-citationYan, X., Tian, X., Wu, Z., & Han, W. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01671 · Cited by 45 · see citing works
Immune Checkpoint Blockade for Advanced NSCLC: A New Landscape for Elderly Patients
Perrotta, F., Rocco, D., Vitiello, F., Palma, R. D., Guerra, G., Luca, A. D., Navani, N., & Bianco, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092258 · Cited by 43 · see citing works
“Cytotoxic T cells in the elderly have an increased expression of CD57, a marker of senescence, that lead to less anti-tumoral immunogenic activity [46] and lower level of perforine and granzyme, essential for cytotoxic activity [47].”
BackgroundSingle-cell atlas of the aging mouse colon
Širvinskas, D., Omrani, O., Lu, J. N., Rasa, S. M. M., Křepelová, A., Adam, L., Käppel, S., Sommer, F., & Neri, F. (2022) · iScience · doi:10.1016/j.isci.2022.104202 · Cited by 42 · see citing works
de Moura, R. G., Covre, L. P., Fantecelle, C. H., Gajardo, V. A. T., Cunha, C. B., Stringari, L. L., Belew, A. T., Daniel, C. B., von Zeidler, S. V., Tadokoro, C. E., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.632667 · Cited by 39 · see citing works
“Senescent CD8 T cells do not express high levels of PD-1 reinforcing the possibility that senescent and exhausted CD8+ T cells are distinct populations, as suggested previously (24).”
BackgroundMethodInfluentialSelf-citationTargeting T-cell metabolism to boost immune checkpoint inhibitor therapy
Li, H., Zhao, A., Li, M., Shi, L., Han, Q., & Hou, Z. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1046755 · Cited by 39 · see citing works
“The inhibition of PD-1 and p38 signaling pathways together may enable the proliferation of the TEMRA (effector memory T cells expressing CD45RA) subset (66).”
BackgroundSeidel, J. A., Vukmanovic‐Stejic, M., Müller-Durovic, B., Patel, N. P., Fuentes‐Duculan, J., Henson, S. M., Krueger, J. G., Rustin, M. H. A., Nestle, F. O., Lacy, K. E., et al. (2018) · Clinical & Experimental Immunology · doi:10.1111/cei.13189 · Cited by 38 · see citing works
Self-citationT-cell senescence: A crucial player in autoimmune diseases
Lu, Y., Ruan, Y., Pan, H., Rui, K., Liu, Q., Wang, S., & Cui, D. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109202 · Cited by 37 · see citing works
The central role of DNA damage in immunosenescence
Kell, L., Simon, A. K., Alsaleh, G., & Cox, L. S. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1202152 · Cited by 38 · see citing works
“…highly cytotoxic and, much like senescent fibroblasts, produce a SASP with immune-active components (namely, TNF-α and IFN-γ) after short-term activation, that may contribute to the low-grade inflammatory environment in older people (Henson et al., 2014; Henson et al., 2015; Akbar et al., 2016).”
BackgroundT cell senescence: a new perspective on immunotherapy in lung cancer
Huang, M., Wang, Y., Fang, L., Liu, C., Feng, F., Liu, L., & Sun, C. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1338680 · Cited by 37 · see citing works
Enhancing immunity during ageing by targeting interactions within the tissue environment
Bracken, O. V., Maeyer, R. P. H. D., & Akbar, A. N. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01126-9 · Cited by 40 · see citing works
“The ageing immune system Interactions of immune cells with senescent tissue cells Targeting tissue environments with senolytics and senomorphics to enhance immunity”
Self-citationΛιούλιος, Γ., Fylaktou, A., Papagianni, A. A., & Stangou, M. J. (2021) · Clinical Immunology · doi:10.1016/j.clim.2021.108685 · Cited by 36 · see citing works
The role of TEMRA cell-mediated immune senescence in the development and treatment of HIV disease
Guo, L., Liu, X., & Su, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1284293 · Cited by 34 · see citing works
“These cells exhibit various characteristics of advanced differentiation, such as a low proliferative activity, high levels of DNA damage and the loss of telomerase activity (31 – 33).”
BackgroundAdaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens
Pita‐López, M. L., Pera, A., & Solana, R. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00616 · Cited by 33 · see citing works
“This memory subpopulation is interesting, because the senescence of human TTE CD8+ T-cells is stringently controlled by distinct and reversible cell signaling events (31).”
BackgroundImpact of Age-, Cancer- and Treatment-Driven Inflammation on T Cell Function and Immunotherapy
Quinn, K. M., Kartikasari, A. E. R., Cooke, R. E., Koldej, R. M., Ritchie, D. S., & Plebanski, M. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.5mr0520-466r · Cited by 31 · see citing works
Immunotherapy in older patients with hepatocellular carcinoma
Lyu, N., Yi, J., & Zhao, M. D. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.11.024 · Cited by 29 · see citing works
IL-15 Harnesses Pro-inflammatory Function of TEMRA CD8 in Kidney-Transplant Recipients
Tilly, G., Doan-Ngoc, T.-M., Yap, M., Caristan, A., Jacquemont, L., Danger, R., Cadoux, M., Bruneau, S., Giral, M., Guérif, P., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00778 · Cited by 28 · see citing works
T-cell Senescence in the Tumor Microenvironment
Huang, L., Zhang, C., Jiang, A., Lin, A., Zhu, L., Mou, W., Zeng, D., Liu, Z., Tang, B., Zhang, J., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-0894 · Cited by 27 · see citing works
Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?
Hieber, C., Grabbe, S., & Bros, M. (2023) · Biomolecules · doi:10.3390/biom13071085 · Cited by 28 · see citing works
Admasu, T. D., & Yu, J. S. (2025) · Aging Cell · doi:10.1111/acel.70055 · Cited by 25 · see citing works
“Although TEMRA cells are often considered as senescent T cells, their precise role in immunosenescence remains under investigation (Henson et al. 2015).”
Senescent Stromal Cells in the Tumor Microenvironment: Victims or Accomplices?
Ye, M., Huang, X., Wu, Q., & Liu, F. (2023) · Cancers · doi:10.3390/cancers15071927 · Cited by 26 · see citing works
CD28null T cells in aging and diseases: From biology to assessment and intervention
Guan, Y., Cao, M., Wu, X., Yan, J., Hao, Y., & Zhang, C. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.111807 · Cited by 26 · see citing works
The convergence of senescence and nutrient sensing during lymphocyte ageing
Akbar, A. N. (2016) · Clinical and Experimental Immunology · doi:10.1111/cei.12876 · Cited by 23 · see citing works
Directing T-Cell Immune Responses for Cancer Vaccination and Immunotherapy
Smith, P. L., Piadel, K., & Dalgleish, A. G. (2021) · Vaccines · doi:10.3390/vaccines9121392 · Cited by 23 · see citing works
Co-Expression of TIGIT and Helios Marks Immunosenescent CD8+ T Cells During Aging
Pieren, D. K. J., Smits, N. A. M., Postel, R. J., Kandiah, V., de Wit, J., van Beek, J., van Baarle, D., & Guichelaar, T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.833531 · Cited by 22 · see citing works
“2), CD27-BV510 (clone O323), and CD57 (clone HCD57) all from Biolegend, CD8-BUV395 (clone RPA-T8, BD Horizon), TIGIT-PE-eFluor610 (clone MBSA43, eBioscience), CD226-BV785 (clone DX11, BD Optibuild), and KLRG1-PerCP-eFluor710 (clone 13F12F2, Invitrogen).”
BackgroundInfluentialCheckpoint Inhibitors for Non-Small Cell Lung Cancer Among Older Adults
Elias, R., Morales, J. K., & Presley, C. J. (2017) · Current Oncology Reports · doi:10.1007/s11912-017-0619-0 · Cited by 22 · see citing works
Accardi, G., Aprile, S., Candore, G., Caruso, C., Cusimano, R., Cristaldi, L., Bona, D. D., Duro, G., Galimberti, D., Gambino, C. M., et al. (2019) · Current Pharmaceutical Design · doi:10.2174/1381612825666190313115233 · Cited by 22 · see citing works
Jo, N., Zhang, R., Ueno, H., Yamamoto, T., Weiskopf, D., Nagao, M., Yamanaka, S., & Hamazaki, Y. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.719342 · Cited by 21 · see citing works
“TEMRA cells include CD28− terminally differentiated T cells with compromised proliferation capacities, as well as CD57 senescent T cells with a high potential for inflammatory cytokine production (Brenchley et al., 2003; Henson et al., 2015).”
BackgroundAging-associated immune system changes in multiple myeloma: The dark side of the moon.
Visram, A., & Kourelis, T. (2021) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2021.100494 · Cited by 19 · see citing works
Garnica, M., Aiello, A., Ligotti, M. E., Accardi, G., Arasanz, H., Bocanegra, A., Blanco, E., Calabrò, A., Chocarro, L., Echaide, M., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179797 · Cited by 19 · see citing works
“Specifically, an increase in TEMRA CD8+ T cells (see Section 2.1) is associated with worse memory responses against SARS-CoV-2, as well as a compromised antibody response [127].”
BackgroundInfluentialDecoding T cell senescence in cancer: Is revisiting required?
Magkouta, S., Markaki, E., Evangelou, K., Petty, R., Verginis, P., & Gorgoulis, V. G. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.11.003 · Cited by 17 · see citing works
Liu, T., Ding, S., Dang, J., Wang, H., Chen, J., & Li, G. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.07.45 · Cited by 17 · see citing works
“Expression of PD-1 was found to be increased in T cells of older adults and its blockade did not restore T cell activity to the same extent as in younger adults (36-38).”
ResultParticipation of T cells in generating immune protection against cancers
Deo, A. S., Shrijana, Sruthika, S. U., Karun, S., Bisaria, K., & Sarkar, K. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155534 · Cited by 17 · see citing works
Neoadjuvant chemotherapy modulates exhaustion of T cells in breast cancer patients
Rodríguez, I. J., Bernal-Estévez, D. A., Llano-León, M., Bonilla, C., & Parra-López, C. (2023) · PLoS ONE · doi:10.1371/journal.pone.0280851 · Cited by 16 · see citing works
“Senescence and exhaustion are characterized by a decrease in T cell proliferative capacity [16, 32].”
BackgroundInclusion Body Myositis and Neoplasia: A Narrative Review
Damian, L. O., Login, C., Solomon, C. M., Belizna, C. C., Encică, S., Urian, L. G., Jurcuț, C., Stancu, B., & Vulturar, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137358 · Cited by 15 · see citing works
Xia, T., Zhou, Y., An, J., Cui, Z. G., Zhong, X., Cui, T., Lv, B., Zhao, X., & Gao, X. (2024) · Aging Cell · doi:10.1111/acel.14317 · Cited by 15 · see citing works
“…to the scaffold protein TAB1, which results in p38 autophosphorylation and inhibits telomerase activity and cells proliferation potential (Henson et al., 2015 ; Lanna et al., 2014 ). p38, ERK, and JNK are localized within a separate inhibi - tory signaling complex that also contains the…”
BackgroundZhao, B., Zhao, H., & Zhao, J. (2018) · International Journal of Cancer · doi:10.1002/ijc.31813 · Cited by 15 · see citing works
Ding, Y., Lei, S., Wang, L., Tang, L., Zhang, Y., Liao, Y., Deng, X., Li, Y., Gong, Y., & Li, Y. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107925 · Cited by 14 · see citing works
Senescent T Cells in Age-Related Diseases
Yu, P.-J., Zhou, M. L., Liu, Y., & Du, J. (2024) · Aging and Disease · doi:10.14336/ad.2024.0219 · Cited by 14 · see citing works
CD8+ T Cells in Immunotherapy, Radiotherapy, and Chemotherapy
Wang, W., Green, M. D., Liu, J. R., Lawrence, T. S., & Zou, W. (2017) · Springer eBooks · doi:10.1007/978-3-319-62431-0_3 · Cited by 13 · see citing works
Regulation of cell function and identity by cellular senescence
Huna, A., Massemin, A., Makulyte, G., Flaman, J., Martin, N., & Bernard, D. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202401112 · Cited by 13 · see citing works
“Interestingly, they produce more perforin and granzyme cytotoxic proteins and secrete higher levels of inflammatory molecules (IFN-γ and TNF-α ), supporting their increased function upon cellular senescence (Henson et al., 2015).”
BackgroundHuang, L., Li, X., Li, Z., Zhu, H., Han, Y., Zeng, J., Wen, M., & Zeng, H. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.111055 · Cited by 13 · see citing works
Immune senescence: A key player in cancer biology
Yang, Y., Fan, L., Li, M., & Wang, Z. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.12.001 · Cited by 13 · see citing works
T-cell lymphocytes’ aging clock: telomeres, telomerase and aging
Chebly, A., Khalil, C., Kuzyk, A. C., Beylot-Barry, M., & Chevret, E. (2023) · Biogerontology · doi:10.1007/s10522-023-10075-6 · Cited by 13 · see citing works
Wang, X., Guo, D. H., He, C., Wang, X., Yi, W., Zhang, F., Wang, L., & Yang, Y. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04360-z · Cited by 12 · see citing works
“Accordingly, inhibition of the p38 MAPK pathway was found to enhance CD8 T EMRA proliferation and telomerase activity while suppressing TNF-α secretion [57].”
Landscape of targeted therapies for lung squamous cell carcinoma
Chen, Q., Zheng, X.-S., Cheng, W., & Li, J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1467898 · Cited by 12 · see citing works
Chang, Y., Cao, W., Lu, L., Han, Y., Lin, Q., Zhou, B., & Li, T. (2024) · Aging · doi:10.18632/aging.205985 · Cited by 11 · see citing works
Immunosenescence: Molecular Mechanisms, Diseases, and Therapeutic Innovations
Gong, N., Pan, X., Deng, Y., Che, J., Bao, J., Wang, M., Xu, C., Liu, X., & Shi, Y. (2025) · MedComm · doi:10.1002/mco2.70515 · Cited by 11 · see citing works
MIF modulates p38/ERK phosphorylation via MKP-1 induction in sarcoidosis
Talreja, J., Peng, C., & Samavati, L. (2023) · iScience · doi:10.1016/j.isci.2023.108746 · Cited by 9 · see citing works
“50 Our results show that exogenous MIF decreased the p38 phosphorylation andpotentiatedtheIFN-g production.”
BackgroundSLAMF7 defines subsets of human effector CD8 T cells
Kared, H., Tan, C. T. Y., Narang, V., Tan, S. W., Chin, H. X., Wei, A. T. S., Lum, J., Ruíz-Mateos, E., Rajasuriar, R., Kamarulzaman, A., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-80971-5 · Cited by 9 · see citing works
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CD8+ T-cell senescence: no role for mTOR
Henson, S. M. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150092 · Cited by 9 · see citing works
Self-citationLolli, C., Altavilla, A., Conteduca, V., Farolfi, A., Casadei, C., Schepisi, G., Banna, G. L., & Giorgi, U. D. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103036 · Cited by 9 · see citing works
- Authors
- Henson, S. M., Macaulay, R., Riddell, N. E., Nunn, C. J., & Akbar, A. N.
- Affiliations
- Division of Infection and Immunity University College London London UK
- University College London (GB)
- Corresponding author
- Akbar, Arne N.
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2015-03-30
- Volume
- 45
- Issue
- 5
- Pages
- 1441-1451
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W2169203113
- Cited by
- 146
- References
- 52
- Citations by year
- 2026: 3 · 2025: 16 · 2024: 25 · 2023: 14 · 2022: 12 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 14 · 2017: 13 · 2016: 10 · 2015: 1
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- PD-1 signaling, p38 MAPK, CD8+ T cells, T cell senescence, effector memory T cells, CD45RA, T cell proliferation, telomerase activity, γH2AX, DNA damage response, TNF-alpha secretion, immunosenescence
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Cell Differentiation, Histones, Humans, Immunologic Memory, T-Lymphocyte Subsets, Cytokines, Cellular Senescence, Leukocyte Common Antigens, CD8-Positive T-Lymphocytes, Telomerase, MAP Kinase Signaling System, p38 Mitogen-Activated Protein Kinases, Cell Proliferation, Young Adult, Programmed Cell Death 1 Receptor
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