The DOI matches its Crossref record; 32 of the 33 references it cites were found in a registry or an index.
Loss of CD28 expression on T lymphocytes: A marker of replicative senescence
Abstract
The CD28 molecule, a disulfide-linked homodimer expressed on peripheral T cells and thymocytes, mediates an essential costimulatory signal following engagement of the T cell receptor (TCR). Increased proportions of CD28- T cells have been observed during aging and in situations of chronic immune stimulation, but the origin and functional characteristics of these cells have been unclear. T cells which reach replicative senescence in culture after multiple rounds of cell division have shortened telomeres, respond poorly to stress stimuli, and no longer express CD28, suggesting that CD28- T cells observed in vivo may be the progeny of memory cells which have been repeatedly stimulated. This review describes the features of T cell replicative senescence, presents several possible mechanisms for the generation of senescent T cells in vivo, and proposes that replicative senescence may explain immune exhaustion.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“These oligoclonal expanded CD8 + memory T cells are further distinguished in humans by loss of expression of the CD28 co-stimulatory molecule (47,48) and impaired immune function.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [47]
Citations
Cites
A Theory of Self-Nonself Discrimination
Bretscher, P., & Cohn, M. (1970) · Science · doi:10.1126/science.169.3950.1042 · Cited by 1,755
The B7 and CD28 receptor families
June, C. H., Bluestone, J. A., Nadler, L. M., & Thompson, C. B. (1994) · Immunology Today · doi:10.1016/0167-5699(94)90080-9 · Cited by 1,296
Telomere loss: mitotic clock or genetic time bomb?
Harley, C. B. (1991) · Mutation Research/DNAging · doi:10.1016/0921-8734(91)90018-7 · Cited by 1,139
Induction of Bystander T Cell Proliferation by Viruses and Type I Interferon in Vivo
Tough, D. F., Borrow, P., & Sprent, J. (1996) · Science · doi:10.1126/science.272.5270.1947 · Cited by 1,081
Posnett, D. N., Sinha, R., Kabak, S., & Russo, C. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.2.609 · Cited by 761
Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes.
Vaziri, H., Schächter, F., Uchida, I. A., Wei, L., Zhu, X., Effros, R. B., Cohen, D., & Harley, C. (1993) · PubMed · Cited by 737
Self-citationReplicative Senescence: Implications for in Vivo Aging and Tumor Suppression
Smith, J. R., & Pereira-Smith, O. M. (1996) · Science · doi:10.1126/science.273.5271.63 · Cited by 547
Effros, R. B., Allsopp, R., Chiu, C.-P., Hausner, M. A., Hirji, K., Wang, L., Harley, C. B., Villeponteau, B., West, M. D., & Giorgi, J. V. (1996) · AIDS · doi:10.1097/00002030-199607000-00001 · Cited by 457
Self-citationRegulated expression of telomerase activity in human T lymphocyte development and activation.
Weng, N., Levine, B. L., June, C. H., & Hodes, R. J. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.6.2471 · Cited by 401
CD28- T lymphocytes. Antigenic and functional properties
Azuma, M., Phillips, J. H., & Lanier, L. L. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.150.4.1147 · Cited by 392
Cited by
Sorted by citations
Items 101–175 of 175
Lymphocyte Modulation in a Baboon Model of Immunosenescence
Jayashankar, L., Brasky, K. M., Ward, J. A., & Attanasio, R. (2003) · Clinical and Vaccine Immunology · doi:10.1128/cdli.10.5.870-875.2003 · Cited by 21
Mahnke, Y. D., Saqr, A., Hazenfeld, S., Brady, R. C., Roederer, M., & Subbramanian, R. A. (2011) · Vaccine · doi:10.1016/j.vaccine.2011.09.019 · Cited by 20
D’Abramo, A., Zingaropoli, M. A., Oliva, A., D’Agostino, C., Moghazi, S. A., Luca, G. D., Iannetta, M., d’Ettorre, G., Ciardi, M. R., Mastroianni, C. M., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149601 · Cited by 20
Limited Blood Transfusion Does Not Impact Survival in Octogenarians Undergoing Cardiac Operations
Yun, J. J., Helm, R. E., Kramer, R. S., Leavitt, B. J., Surgenor, S. D., DiScipio, A. W., Dacey, L. J., Baribeau, Y. R., Russo, L., Sardella, G. L., et al. (2012) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2012.06.059 · Cited by 19
The Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease
Ayoub, M., Jaoude, C. A., Ayoub, M., Hamadé, A., & Rima, M. (2025) · Immunology · doi:10.1111/imm.70036 · Cited by 25
Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers
Rivet, C. A., Hill, A. S., Lu, H., & Kemp, M. L. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.003921 · Cited by 18
Brzezińska, A., Magalska, A., & Sikora, E. (2003) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(03)00012-5 · Cited by 18
Thymectomy in Early Childhood: A Model for Premature T Cell Immunosenscence?
Zlamy, M., & Prelog, M. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0864 · Cited by 20
Sheu, T.-T., Chiang, B., Yen, J.-H., & Lin, W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089379 · Cited by 18
Alberro, A., Osorio-Querejeta, I., Sepúlveda, L., Fernández‐Eulate, G., Mateo‐Abad, M., Muñoz‐Culla, M., Carregal‐Romero, S., Matheu, A., Vergara, I., de Munaín, A. L., et al. (2019) · Aging · doi:10.18632/aging.102517 · Cited by 21
Wikby, A., Johansson, B. E. A., & Ferguson, F. G. (2002) · Advances in cell aging and gerontology · doi:10.1016/s1566-3124(02)13001-x · Cited by 18
Hoeks, C., Vanheusden, M., Peeters, L. M., Stinissen, P., Broux, B., & Hellings, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115660 · Cited by 17
Bartolome, M. J., Martı́nez-Taboda, V. M., López‐Hoyos, M., Blanco, R., & Rodrı́guez-Valverde, V. (2001) · PubMed · Cited by 16
Proliferation and apoptosis of human T cells during replicative senescence--a critical approach.
Jaruga, E., Skierski, J., Radziszewska, E., & Sikora, E. (2000) · Acta Biochimica Polonica · doi:10.18388/abp.2000_4009 · Cited by 16
Wick, G., & Grubeck‐Loebenstein, B. (1997) · Developmental & Comparative Immunology · doi:10.1016/s0145-305x(97)00025-6 · Cited by 16
Veel, E., Westera, L., van Gent, R., Bont, L., Otto, S. A., Ruijsink, B., Rabouw, H. H., Mudrikova, T., Wensing, A. M. J., Hoepelman, A. I. M., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00572 · Cited by 12
Age-related changes in mature CD4+ T cells: cell cycle analysis
Hale, T. J., Richardson, B. C., Sweet, L. I., McElligott, D. L., Riggs, J. E., Chu, E. B., Glynn, J. M., Lafrenz, D., Ernst, D. N., Rochford, R. A., et al. (2002) · Cellular Immunology · doi:10.1016/s0008-8749(03)00007-8 · Cited by 13
Jallah, B. P., & Kuypers, D. R. J. (2024) · Drugs & Aging · doi:10.1007/s40266-024-01100-5 · Cited by 12
Prelog, M., Schönlaub, J., Würzner, R., Koppelstaetter, C., Almanzar, G., Brunner, A., Gasser, M., Prommegger, R., Haeusler, G., Kapelari, K., et al. (2013) · BMC Endocrine Disorders · doi:10.1186/1472-6823-13-34 · Cited by 12
High-dimensional comparison of monocytes and T cells in post-COVID and idiopathic pulmonary fibrosis
Bingham, G. C., Muehling, L. M., Li, C., Huang, Y., Ma, S., Abebayehu, D., Noth, I., Sun, J., Woodfolk, J. A., Barker, T. H., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1308594 · Cited by 13
Quantitative alterations of CD8+ T cells in juvenile idiopathic arthritis patients in remission
Prelog, M., Schwarzenbrunner, N., Tengg, E., Sailer‐Höck, M., Kern, H., Zimmerhackl, L. B., & Brunner, J. (2008) · Clinical Rheumatology · doi:10.1007/s10067-008-1057-z · Cited by 10
Leposavić, G., Pilipović, I., & Nanut, M. P. (2011) · NeuroImmunoModulation · doi:10.1159/000329499 · Cited by 11
Kapetanovic, S., Aaron, L. A., Montepiedra, G., Anthony, P., Thuvamontolrat, K., Pahwa, S. G., Burchett, S. K., Weinberg, A., & Kovács, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120474 · Cited by 10
Sun, Y., Xie, J., Anyalebechi, J. C., Chen, C., Sun, H. Y., Xue, M., Liang, Z., Morrow, K. N., Coopersmith, C. M., & Ford, M. L. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000595 · Cited by 10
Aging of the Immune System Across Different Species
Nikolich-Žugich, J., & Čičin-Šain, L. (2010) · The Comparative Biology of Aging · doi:10.1007/978-90-481-3465-6_15 · Cited by 9
Friedman, J. S., Alpdoğan, Ö., van den Brink, M. R. M., Liu, C., Hurwitz, D., Boyd, A. S., Kupper, T. S., & Burakoff, S. J. (2004) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2004.03.005 · Cited by 9
Zhang, L., Liang, H., Guan, H., & LIU, H. (2015) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2015.2295 · Cited by 8
Impact of culture conditions on the proliferative lifespan of human T cells in vitro
Röth, A., Schneider, L., Himmelreich, H., Baerlocher, G. M., & Dührsen, U. (2006) · Cytotherapy · doi:10.1080/14653240601113197 · Cited by 8
Gardner, J. K., Jackaman, C., Mamotte, C. D. S., & Nelson, D. J. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00337 · Cited by 7
Francesco, D. D., Sabin, C. A., Reiss, P., & Kootstra, N. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.581616 · Cited by 7
Recreational Dance Practice Modulates Lymphocyte Profile and Function in Diabetic Women
Passos, M. E. P., Borges, L., dos Santos-Oliveira, L. C., Alecrim, A. L., Lobato, T. B., de Oliveira, H. H., Momesso, C. M., Diniz, V. L. S., Iser‐Bem, P. N., Manoel, R., et al. (2020) · International Journal of Sports Medicine · doi:10.1055/a-1309-2037 · Cited by 7
Srivastava, R., Dhanushkodi, N. R., Prakash, S., Coulon, P.-G. A., Vahed, H., Zayou, L., Quadiri, A., & BenMohamed, L. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.26.501655 · Cited by 6
Immune cell phenotype and function patterns across the life course in individuals from rural Uganda
Nalwoga, A., Nakibuule, M., Roshan, R., Mbonye, M. K., Miley, W., Whitby, D., Newton, R., Rochford, R. A., & Cose, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1356635 · Cited by 5
Accelerated T-cell senescence and persistent inflammation in older adults with rheumatoid arthritis
Cezar, C. D., Scholl, J. N., Rabelo, C. F., Madruga, M. P., Silva, P. L., Grün, L. K., Engroff, P., Bressanim, A. C. M., Scherer, R. T., Schwanke, C. H. A., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115518 · Cited by 5
Immunosenescence, Inflammaging, and Their Implications for Cancer and Anemia
Paudel, S., Sharma, P., & Puri, N. (2019) · Springer eBooks · doi:10.1007/978-981-13-3585-3_14 · Cited by 6
Compromised levels of CD6 and reduced T cell activation in the aged immune system
Kureel, A. K., Saini, S., Singh, B., Singh, K., & Rai, A. K. (2021) · Biomarkers · doi:10.1080/1354750x.2021.1921030 · Cited by 5
Comparative Proteome Analysis of Splenic Lymphocytes in Senescence-Accelerated Mice
Luo, Y., Li, Y., Lin, C. X., Ma, H., Zhang, J., Wu, S., Wang, X., Gao, Y., Liu, Y., & Zheng, D. (2009) · Gerontology · doi:10.1159/000225958 · Cited by 5
Cancer-Associated Immune Deficiency: A Form of Accelerated Immunosenescence?
Chang, C., Wu, C., & Lu, Y. (2012) · InTech eBooks · doi:10.5772/24367 · Cited by 5
Hearps, A. C., Schafer, K. R., High, K. P., & LANDAY, A. L. (2015) · Springer eBooks · doi:10.1007/978-3-319-23246-1_17 · Cited by 5
Aging‐Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment
Udumula, M. P., Anjaly, K., Rashid, F., Nematullah, M., Singh, H., Bhardwaj, T., Hijaz, M., Giri, S., Chini, E. N., Gibson, H. M., et al. (2026) · Aging Cell · doi:10.1111/acel.70510 · Cited by 4
Interplay between CD28 and PD-1 in T cell immunotherapy
Jafri, Z., Zhang, J., O’Meara, C. H., Joshua, A. M., Parish, C. R., & Khachigian, L. M. (2024) · Vascular Pharmacology · doi:10.1016/j.vph.2024.107461 · Cited by 5
Almanzar, G., Zlamy, M., Koppelstaetter, C., Brunner, A., Jeller, V., Duftner, C., Dejaco, C., Brunner, J., & Prelog, M. (2013) · Journal of Medical Case Reports · doi:10.1186/1752-1947-7-135 · Cited by 3
Macrophage-Induced Exacerbation of Nasopharyngeal Inflammatory Lymphocytes in COVID-19 Disease
Ayass, M., Tripathi, T., Griko, N., Nair, R. R., Zhang, J., Zhu, K., Cao, W., Pashkov, V., Okyay, T., Singh, S., et al. (2023) · COVID · doi:10.3390/covid3040041 · Cited by 2
Telomerase and Human Disease: The Beginnings of the Ends?
Fossel, M., & Flanary, B. E. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0873 · Cited by 2
P-glycoprotein expression in the cells of the immune system during aging
Gupta, S. (2003) · Clinical and Applied Immunology Reviews · doi:10.1016/s1529-1049(03)00003-5 · Cited by 2
Biomarkers of Replicative Senescence Revisited
Nehlin, J. O. (2016) · Healthy ageing and longevity · doi:10.1007/978-3-319-26239-0_12 · Cited by 2
Immunosenescence Modulation by Vaccination
McElhaney, J. E. (2019) · Springer eBooks · doi:10.1007/978-3-319-99375-1_71 · Cited by 2
Casado, J. G., DelaRosa, O., Peralbo, E., Tarazona, R., & Solana, R. (2002) · Advances in cell aging and gerontology · doi:10.1016/s1566-3124(02)13007-0 · Cited by 2
International conference on biomedical aspects of aging research
SARA Study Group, Cristofalo, V. J., Crepaldi, G., Evans, J. G., Rowe, J. W., Kahn, R. L., Kirkwood, T. B. L., Hayflick, L., Austad, S. N., BENEDICTIS, G. D., et al. (1998) · Aging Clinical and Experimental Research · doi:10.1007/bf03339649 · Cited by 2
Self-citationImmunosenescence Modulation by Vaccination
McElhaney, J. E. (2017) · Springer eBooks · doi:10.1007/978-3-319-64597-1_71-1 · Cited by 1
Katsuumi, G., & Minamino, T. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822514-1.00007-9 · Cited by 1
Bingham, G. C., Muehling, L. M., Li, C., Huang, Y., Abebayehu, D., Noth, I., Sun, J., Woodfolk, J. A., Barker, T. H., & Bonham, C. A. (2022) · medRxiv · doi:10.1101/2022.09.30.22280468 · Cited by 2
Witkowski, J. M. (2008) · Springer eBooks · doi:10.1007/978-0-387-76842-7_8 · Cited by 1
Riddell, N. E. (2010) · University of Birmingham Institutional Research Archive (University of Birmingham) · Cited by 1
T cells and costimulatory factors in myasthenia gravis
Kakoulidou, M. (2005) · Figshare
Spielmann, G. (2026) · Edinburgh Napier Research Repository (Edinburgh Napier University) · doi:10.17869/enu.192070
Larbi, A., & Fülöp, T. (2004) · Neuroimmune biology · doi:10.1016/s1567-7443(04)80006-1
Witkowski, J. M. (2009) · Springer eBooks · doi:10.1007/978-1-4020-9063-9_13
Immunosenescence Modulation by Vaccination
McElhaney, J. E. (2009) · Springer eBooks · doi:10.1007/978-1-4020-9063-9_71
T cells and their role in Polymyalgia Rheumatica and Giant Cell Arteritis
Blažíčková, S., & Rovenský, J. (2010) · Springer eBooks · doi:10.1007/978-3-211-99359-0_4
Characterization of an autoimmune gene expression signature.
Maas, K. H. (2006)
Broli, G. (2013) · BIBSYS Brage (BIBSYS (Norway))
Immune System, Immunosenescence and Immunisation in the Elderly
Nagaratnam, N., & Nagaratnam, S. A. (2018) · Springer eBooks · doi:10.1007/978-3-319-96998-5_7
Differential Maintenance, Function, and Transcriptional Profile of CD8⁺ T cells with Age
Renkema, K. R. (2013) · UA Campus Repository (The University of Arizona)
Witkowski, J. M., & Fülöp, T. (2018) · Springer eBooks · doi:10.1007/978-3-319-64597-1_13-1
Bucci, L., Ostan, R., Capri, M., Salvioli, S., Cevenini, E., Celani, L., Monti, D., & Franceschi, C. (2009) · Springer eBooks · doi:10.1007/978-1-4020-9063-9_45
Witkowski, J. M., & Fülöp, T. (2019) · Springer eBooks · doi:10.1007/978-3-319-99375-1_13
Kern, F., & Bano, A. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727486481.793557995
T cell exhaustion and aging: is replicative senescence relevant?
Effros, R. B. (2002) · Advances in cell aging and gerontology · doi:10.1016/s1566-3124(02)13016-1
Self-citationBeatty, G. L., Smith, J. S., Reshef, R., Patel, K. P., Colligon, T. A., Vance, B. A., Frey, N. V., Johnson, F. B., Porter, D., & Vonderheide, R. H. (2023) · doi:10.1158/1078-0432.c.6518094
Beatty, G. L., Smith, J. S., Reshef, R., Patel, K. P., Colligon, T. A., Vance, B. A., Frey, N. V., Johnson, F. B., Porter, D. L., & Vonderheide, R. H. (2023) · doi:10.1158/1078-0432.c.6518094.v1
Interleukin-10 augments human endogenous retroviral E1B variant of cd5 in aged T cells
Singh, B., Kumari, S., Kureel, A. K., Shah, A., Katiyar, S., Chaturvedi, C. P., Singh, K., & Rai, A. K. (2025) · Blood Research · doi:10.1007/s44313-025-00080-8
Lenalidomide targets the T-cell co-stimulatory pathway to mediate immune modulation
McDaniel, J. M. (2012) · Digital Commons - University of South Florida (University of South Florida)
The Imbalance Between Tumor Immunosurveillance and Tumor Immune Escape in Glioblastoma
MacDonald, S. J., Drill, M., Jayakrishnan, P. C., Sequeira, R. P., O’Brien, T. J., Jeffree, R. L., & Monif, M. (2026) · Immunology and Cell Biology · doi:10.1111/imcb.70153
Srivastava, R., Prakash, S., Karan, S., & BenMohamed, L. (2026) · Viruses · doi:10.3390/v18090940
Metadata
- Authors
- Effros, R. B.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Effros, Rita B.
- ORCID
- Effros, Rita B.
- Venue
- Developmental & Comparative Immunology
- Publisher
- Elsevier BV
- Published
- 1997-11
- Volume
- 21
- Issue
- 6
- Pages
- 471-478
- ISSN
- 0145-305X (ISSN-L)
- OpenAlex
- W2032253593
- Cited by
- 175
- References
- 33
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 2 · 2016: 4 · 2015: 10 · 2014: 3 · 2013: 9 · 2012: 5
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Developmental & Comparative Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-10415, P60AG010415)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- CD28, immunosenescence, immune exhaustion, T cell costimulation, telomere shortening, memory T cells, chronic immune stimulation, T cell receptor signaling
- MeSH terms
- Cell Division, Humans, T-Lymphocytes, Biomarkers, Telomere, Cellular Senescence, CD28 Antigens
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review