Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance
Open accessAbstract
A key feature of human natural killer (NK) cells, which enables efficient recognition of infected and malignant target cells, is the expression of HLA class I-specific receptors of the KIR and NKG2 gene families. Cell-to-cell variability in receptor expression leads to the formation of complex NK cell repertoires. As outlined here, NK cells go through major changes from newborns to adults characterized by downregulation of the inhibitory NKG2A receptor and concomitant upregulation of KIR family members. This process is completed in young adults, and in the majority of individuals, KIR/NKG2A repertoires remain remarkably stable until old age. Nonetheless, age-related factors have the potential to majorly influence the complexity of NK cell repertoires: Firstly infection with HCMV is associated with major clonal expansions of terminally differentiated NKG2C- and KIR-expressing NK cells in certain individuals. Secondly, ineffective hematopoiesis can lead to immature and less diversified NK cell repertoires as observed in myelodysplastic syndrome (MDS), a malignant disease of the elderly. Thus, whereas in the majority of elderly the NK cell compartment appears to be highly stable in terms of function and phenotype, in a minority of subjects a breakdown of NK cell repertoire diversity is observed that might influence immune surveillance and healthy aging.
Integrity signals
Registry
Cites
Statistics
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?
Many immune cell subsets become hyporesponsive to acute challenges with age.
“Thus, many immune cell subsets become hyporesponsive to acute challenges as we age17,19-25.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [21]
In immunosenescence, activating receptor expression of NK cell markers NKP30, NKP46, etc., is reduced, while inhibitory receptor expression of KIR, NKG2C, etc., is increased.
“It should be noted that, in the process of immunosenescence, the activating receptor expression of natural killer (NK) cell markers NKP30, NKP46, etc., is reduced, while the inhibitory receptor expression of KIR, NKG2C, etc., is increased [45, 46].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [45]
Two subpopulations of NK cells, immature CD14+CD56dim and mature CD14+CD56bright, are associated with aging and remodeling of mature NK cell subsets, and reduced expression of activated receptors may promote the escape of NK cells in the elderly.
“Two subpopulations of NK cells, immature CD14+CD56dim and mature CD14+CD56bright, are associated with aging and remodeling of mature NK cell subsets, and the reduced expression of activated receptors may promote the escape of NK cells in the elderly [45].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [45]
Cites
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012
Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015) · International Journal of Cancer · doi:10.1002/ijc.29210 · Cited by 28,766 · see citing works
Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA
Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J. H., Lanier, L. L., & Spies, T. A. (1999) · Science · doi:10.1126/science.285.5428.727 · Cited by 3,000 · see citing works
HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C
Braud, V. M., Allan, D., O'Callaghan, C. A., Söderström, K., D’Andrea, A., Ogg, G. S., Lazetic, S., Young, N. T., Bell, J. I., Phillips, J. H., et al. (1998) · Nature · doi:10.1038/35869 · Cited by 2,226 · see citing works
Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset
Cooper, M. A., Fehniger, T. A., Turner, S. C., Chen, K. S.-M., Ghaheri, B. A., Ghayur, T., Carson, W. E., & Caligiuri, M. A. (2001) · Blood · doi:10.1182/blood.v97.10.3146 · Cited by 1,448 · see citing works
Licensing of natural killer cells by host major histocompatibility complex class I molecules
Kim, S., Poursine‐Laurent, J., Truscott, S. M., Lybarger, L. P., Song, Y.-J., Yang, L., French, A. R., Sunwoo, J. B., Lemieux, S., Hansen, T. H., et al. (2005) · Nature · doi:10.1038/nature03847 · Cited by 1,328 · see citing works
Direct Recognition of Cytomegalovirus by Activating and Inhibitory NK Cell Receptors
Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B., & Lanier, L. L. (2002) · Science · doi:10.1126/science.1070884 · Cited by 1,229 · see citing works
Cosman, D. J., Müllberg, J., Sutherland, C. L., Chin, W. A., Armitage, R. J., Fanslow, W. C., Kubin, M. Z., & Chalupny, N. J. (2001) · Immunity · doi:10.1016/s1074-7613(01)00095-4 · Cited by 1,228 · see citing works
Human NK Cell Education by Inhibitory Receptors for MHC Class I
Anfossi, N., André, P., Guia, S., Falk, C. S., Roetynck, S., Stewart, C. A., Breso, V., Frassati, C., Reviron, D., Middleton, D., et al. (2006) · Immunity · doi:10.1016/j.immuni.2006.06.013 · Cited by 1,207 · see citing works
Imai, K., Matsuyama, S., Miyaké, S., Suga, K., & Nakachi, K. (2000) · The Lancet · doi:10.1016/s0140-6736(00)03231-1 · Cited by 1,189 · see citing works
Age-related changes in lymphocyte development and function
Linton, P. J., & Dorshkind, K. A. (2004) · Nature Immunology · doi:10.1038/ni1033 · Cited by 1,180 · see citing works
HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A
Lee, N., Llano, M., Carretero, M., Ishitani, A., Navarro, F., López‐Botet, M., & Geraghty, D. E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.5199 · Cited by 1,053 · see citing works
Imprint of human cytomegalovirus infection on the NK cell receptor repertoire
Gumá, M., Angulo, A., Vilches, C., Gómez‐Lozano, N., Malats, N., & López‐Botet, M. (2004) · Blood · doi:10.1182/blood-2004-05-2058 · Cited by 865 · see citing works
The Influence of Age on T Cell Generation and TCR Diversity
Naylor, K., Li, G., Vallejo, A. N., Lee, W.-W., Koetz, K., Bryl, E., Witkowski, J., Fulbright, J., Weyand, C. M., & Goronzy, J. J. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.7446 · Cited by 802 · see citing works
Lopez-Vergès, S., Milush, J. M., Pandey, S., York, V. A., Arakawa-Hoyt, J., Pircher, H., Norris, P. J., Nixon, D. F., & Lanier, L. L. (2010) · Blood · doi:10.1182/blood-2010-04-282301 · Cited by 752 · see citing works
Björkström, N. K., Riese, P., Heuts, F. W. H., Andersson, S., Fauriat, C., Ivarsson, M. A., Björklund, A. T., Flodström‐Tullberg, M., Michaëlsson, J., Rottenberg, M. E., et al. (2010) · Blood · doi:10.1182/blood-2010-04-281675 · Cited by 734 · see citing works
Borrego, F., Ulbrecht, M., Weiss, E. H., Coligan, J. E., & Brööks, A. G. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.5.813 · Cited by 726 · see citing works
Comparative studies of human FcRIII-positive and negative natural killer cells.
Nagler, A., Lanier, L. L., Cwirla, S. E., & Phillips, J. H. (1989) · The Journal of Immunology · doi:10.4049/jimmunol.143.10.3183 · Cited by 694 · see citing works
Fernandez, N. C., Treiner, E., Vance, R. E., Jamieson, A. M., Lemieux, S., & Raulet, D. H. (2005) · Blood · doi:10.1182/blood-2004-08-3156 · Cited by 589 · see citing works
Ferlazzo, G., Thomas, D. A., Lin, S., Goodman, K., Morandi, B., Müller, W. A., Moretta, A., & Münz, C. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.3.1455 · Cited by 586 · see citing works
Béziat, V., Liu, L. L., Malmberg, J.-A., Ivarsson, M. A., Sohlberg, E., Björklund, A. T., Retière, C., Sverremark‐Ekström, E., Traherne, J. A., Ljungman, P. T., et al. (2013) · Blood · doi:10.1182/blood-2012-10-459545 · Cited by 503 · see citing works
Romagnani, C., Juelke, K., Falco, M., Morandi, B., D’Agostino, A., Costa, R., Ratto, G. B., Forte, G., Carrega, P., Lui, G., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.4947 · Cited by 494 · see citing works
Björkström, N. K., Lindgren, T., Stoltz, M., Fauriat, C., Braun, M., Evander, M., Michaëlsson, J., Malmberg, K., Klingström, J., Ahlm, C., et al. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20100762 · Cited by 479 · see citing works
Aging of the Immune System: How Much Can the Adaptive Immune System Adapt?
Weng, N. (2006) · Immunity · doi:10.1016/j.immuni.2006.05.001 · Cited by 476 · see citing works
Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections.
Nikolich-Žugich, J. (2008) · Nature reviews. Immunology · doi:10.1038/nri2318 · Cited by 463 · see citing works
Zhang, Y., Wallace, D. L., De Lara, C. M., Ghattas, H., Asquith, B., Worth, A., Griffin, G. E., Taylor, G. P., Tough, D. F., Beverley, P. C. L., et al. (2007) · Immunology · doi:10.1111/j.1365-2567.2007.02573.x · Cited by 376 · see citing works
Human T Cell Aging and the Impact of Persistent Viral Infections
Fülöp, T., Larbi, A., & Pawelec, G. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00271 · Cited by 347 · see citing works
Human NK cells display major phenotypic and functional changes over the life span
Le Garff‐Tavernier, M., Béziat, V., Decocq, J., Siguret, V., Gandjbakhch, F., Pautas, E., Debré, P., Merle‐Beral, H., & Vieillard, V. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00584.x · Cited by 338 · cited 10× · see citing works
“CD16 – +++ [21] → [7, 9]”
BackgroundResultInfluentialElmaagacli, A. H., Steckel, N. K., Koldehoff, M., Hegerfeldt, Y., Trenschel, R., Ditschkowski, M., Christoph, S., Gromke, T., Kordelas, L., Ottinger, H. D., et al. (2011) · Blood · doi:10.1182/blood-2010-08-304121 · Cited by 314 · see citing works
Béziat, V., Dalgård, O., Asselah, T., Halfon, P., Bédossa, P., Boudifa, A., Hervier, B., Theodorou, I. D., Martinot-Peignoux, M., Debré, P., et al. (2011) · European Journal of Immunology · doi:10.1002/eji.201141826 · Cited by 281 · see citing works
Gumá, M., Cabrera, C., Erkizia, I., Bofill, M., Clotet, B., Ruiz, L., & López‐Botet, M. (2006) · The Journal of Infectious Diseases · doi:10.1086/504719 · Cited by 246 · see citing works
Geyh, S., Öz, S., Cadeddu, R.-P., Fröbel, J., Brückner, B., Kündgen, A., Fenk, R. R., Bruns, I., Zilkens, C., Hermsen, D. F., et al. (2013) · Leukemia · doi:10.1038/leu.2013.193 · Cited by 239 · see citing works
Age-related changes in natural killer cell receptors from childhood through old age
Almeida-Oliveira, A., Smith-Carvalho, M., Pôrto, L. C., Cardoso-Oliveira, J., Ribeiro, A. D. S., Falcão, R. R., Abdelhay, E., Bouzas, L. F., Thuler, L. C. S., Ornellas, M. H., et al. (2011) · Human Immunology · doi:10.1016/j.humimm.2011.01.009 · Cited by 223 · see citing works
NK Cell Terminal Differentiation: Correlated Stepwise Decrease of NKG2A and Acquisition of KIRs
Béziat, V., Descours, B., Parizot, C., Debré, P., & Vieillard, V. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011966 · Cited by 218 · see citing works
Hazeldine, J., Hampson, P., & Lord, J. M. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00839.x · Cited by 210 · see citing works
Parham, P., Norman, P. J., Abi‐Rached, L., & Guethlein, L. A. (2012) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2011.0266 · Cited by 200 · see citing works
Ageing is associated with a decline in peripheral blood CD56bright NK cells
Chidrawar, S. M., Khan, N., Chan, Y. L. T., Nayak, L., & Moss, P. A. H. (2006) · Immunity & Ageing · doi:10.1186/1742-4933-3-10 · Cited by 164 · see citing works
The impact of CMV infection on survival in older humans
Pawelec, G., McElhaney, J. E., Aiello, A. E., & Derhovanessian, E. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.04.002 · Cited by 145 · see citing works
Effect of age and CMV on NK cell subpopulations
Campos, C., Pera, A., Sanchez-Correa, B., Alonso, C., Lopez-Fernandez, I., Morgado, S., Tarazona, R., & Solana, R. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.008 · Cited by 128 · see citing works
Schönberg, K., Sribar, M., Enczmann, J., Fischer, J., & Uhrberg, M. (2010) · Blood · doi:10.1182/blood-2010-03-273656 · Cited by 125 · see citing works
Self-citationLutz, C. T., Karapetyan, A., Al-Attar, A., Shelton, B. J., Holt, K. J., Tucker, J. H., & Presnell, S. R. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002732 · Cited by 118 · see citing works
Reciprocal age related change in natural killer cell receptors for MHC class I
Lutz, C. T., Moore, M. B., Bradley, S., Shelton, B. J., & Lutgendorf, S. K. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.01.004 · Cited by 114 · see citing works
Human KIR repertoires: shaped by genetic diversity and evolution
Manser, A. R., Weinhold, S., & Uhrberg, M. (2015) · Immunological Reviews · doi:10.1111/imr.12316 · Cited by 113 · see citing works
Self-citationThe KIR gene family: life in the fast lane of evolution
Uhrberg, M. (2004) · European Journal of Immunology · doi:10.1002/eji.200425743 · Cited by 102 · see citing works
Self-citationEpidemiology, classification and prognosis of adults and children with myelodysplastic syndromes
Germing, U., Aul, C., Niemeyer, C. M., Haas, R. R., & Bennett, J. M. (2008) · Annals of Hematology · doi:10.1007/s00277-008-0499-3 · Cited by 94 · see citing works
Phillips, J. H., & Lanier, L. L. (1985) · The Journal of Experimental Medicine · doi:10.1084/jem.161.6.1464 · Cited by 83 · see citing works
Hejazi, M., Manser, A. R., Frobel, J., Kündgen, A., Zhao, X., Schönberg, K., Germing, U., Haas, R., Gattermann, N., & Uhrberg, M. (2015) · Haematologica · doi:10.3324/haematol.2014.118679 · Cited by 70 · see citing works
Self-citationThe aged nonhematopoietic environment impairs natural killer cell maturation and function
Shehata, H. M., Hoebe, K., & Chougnet, C. A. (2015) · Aging Cell · doi:10.1111/acel.12303 · Cited by 69 · see citing works
Shaping the human NK cell repertoire: an epigenetic glance at KIR gene regulation
Uhrberg, M. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.07.029 · Cited by 67 · see citing works
Self-citationCampos, C., López, N., Pera, A., Gordillo, J. J., Hassouneh, F., Tarazona, R., & Solana, R. (2015) · Biogerontology · doi:10.1007/s10522-015-9581-0 · Cited by 54 · see citing works
Education of hyporesponsive NK cells by cytokines
Juelke, K., Killig, M., Thiel, A., Dong, J., & Romagnani, C. (2009) · European Journal of Immunology · doi:10.1002/eji.200939307 · Cited by 51 · see citing works
Natural killer cell development and maturation in aged mice
Beli, E., Duriancik, D. M., Clinthorne, J. F., Lee, T., Kim, S., & Gardner, E. M. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.11.007 · Cited by 51 · see citing works
Schönberg, K., Fischer, J., Kögler, G., & Uhrberg, M. (2011) · Blood · doi:10.1182/blood-2011-02-334441 · Cited by 49 · see citing works
Self-citationMariani, E. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(03)00058-5 · Cited by 43 · see citing works
The Host Environment Is Responsible for Aging-Related Functional NK Cell Deficiency
Chiu, B., Martin, B. E., Stolberg, V. R., & Chensue, S. W. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301625 · Cited by 42 · see citing works
Bienemann, K., Iouannidou, K., Schönberg, K., Krux, F., Reuther, S., Feyen, O., Bienemann, K., Schuster, F. R., Uhrberg, M., Laws, H. ‐., et al. (2011) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.2011.02591.x · Cited by 36 · see citing works
Self-citationUhrberg, M. (2005) · Leukemia · doi:10.1038/sj.leu.2403705 · Cited by 32 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Role of tumor microenvironment in tumorigenesis
Wang, M., Zhao, J., Zhang, L., Wei, F., Lian, Y., Wu, Y., Gong, Z., Zhang, S., Zhou, J., Cao, K., et al. (2017) · Journal of Cancer · doi:10.7150/jca.17648 · Cited by 1,404 · see citing works
The twilight of immunity: emerging concepts in aging of the immune system
Nikolich-Žugich, J. (2018) · Nature Immunology · doi:10.1038/s41590-017-0006-x · Cited by 1,240 · see citing works
André, P., Denis, C., Soulas, C., Bourbon, C., Lopez, J., Arnoux, T., Bléry, M., Bonnafous, C., Gauthier, L., Morel, A., et al. (2018) · Cell · doi:10.1016/j.cell.2018.10.014 · Cited by 1,229 · see citing works
Immunosenescence: molecular mechanisms and diseases
Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y., & Han, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01451-2 · Cited by 1,023 · see citing works
Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510 · see citing works
Immune ageing at single-cell resolution
Mogilenko, D. A., Shchukina, I., & Artyomov, M. N. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00646-4 · Cited by 392 · see citing works
SARS-CoV-2, COVID-19 and the aging immune system
Bartleson, J. M., Radenkovic, D., Covarrubias, A. J., Furman, D., Winer, D. A., & Verdin, E. (2021) · Nature Aging · doi:10.1038/s43587-021-00114-7 · Cited by 359 · see citing works
Immunosenescence, aging and successful aging
Wang, Y., Chen, D., Han, Y., Gu, Z., & Sun, C. C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.942796 · Cited by 216 · see citing works
Postnatal Innate Immune Development: From Birth to Adulthood
Georgountzou, A., & Papadopoulos, N. G. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00957 · Cited by 204 · see citing works
Immune checkpoint inhibitors and elderly people: A review
Daste, A., Domblides, C., Gross‐Goupil, M., Chakiba, C., Quivy, A., Cochin, V., de Monès, E., Larmonier, N., Soubeyran, P., & Ravaud, A. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.05.044 · Cited by 189 · see citing works
Targeting NK-cell checkpoints for cancer immunotherapy
Muntasell, A., Ochoa, M. C., Cordeiro, L., Berraondo, P., de Cerio, A. L.-D., Cabo, M., López‐Botet, M., & Melero, I. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.01.003 · Cited by 179 · see citing works
Immunosenescence and inflammaging: Mechanisms and role in diseases
Ajoolabady, A., Praticò, D., Tang, D., Zhou, S., Franceschi, C., & Ren, J. T. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102540 · Cited by 160 · see citing works
Activation of immunosuppressive network in the aging process
Salminen, A. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100998 · Cited by 153 · see citing works
Immunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 157 · see citing works
Seddon, J. A., Chiang, S. S., Esmail, H., & Coussens, A. K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02946 · Cited by 127 · see citing works
Advances in NK cell production
Fang, F., Xie, S., Chen, M., Li, Y., Yue, J., Ma, J., Shu, X., He, Y., Xiao, W., & Tian, Z. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00808-3 · Cited by 123 · see citing works
Han, B., Mao, F.-Y., Zhao, Y., Lv, Y.-P., Teng, Y., Duan, M., Chen, W., Cheng, P., Wang, T., Liang, Z.-Y., et al. (2018) · Journal of Immunology Research · doi:10.1155/2018/6248590 · Cited by 119 · see citing works
Overcoming tumor resistance mechanisms in CAR-NK cell therapy
Valeri, A., García-Ortiz, A., Castellano, E., Córdoba, L., Maroto-Martín, E., Encinas, J., Leivas, A., Rı́o, P., & Martínez‐López, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.953849 · Cited by 94 · see citing works
Alcohol, aging, and innate immunity
Boulé, L. A., & Kovacs, E. J. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.4ru1016-450r · Cited by 92 · see citing works
Elyahu, Y., & Monsonego, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101231 · Cited by 91 · see citing works
Targeting immunosenescence and inflammaging: advancing longevity research
Nguyen, T. Q. T., & Cho, K. A. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01527-9 · Cited by 94 · see citing works
Implications of NKG2A in immunity and immune-mediated diseases
Wang, X., Xiong, H., & Ning, Z. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.960852 · Cited by 82 · see citing works
Epigenomic drivers of immune dysfunction in aging
Keenan, C. R., & Allan, R. S. (2018) · Aging Cell · doi:10.1111/acel.12878 · Cited by 76 · see citing works
The twilight of the immune system: The impact of immunosenescence in aging
Feehan, J., Tripodi, N., & Apostolopoulos, V. (2021) · Maturitas · doi:10.1016/j.maturitas.2021.02.006 · Cited by 76 · see citing works
Disruption of the NKG2A:HLA-E Immune Checkpoint Axis to Enhance NK Cell Activation against Cancer
Fisher, J. G., Doyle, A. D. P., Graham, L., Khakoo, S. I., & Blunt, M. D. (2022) · Vaccines · doi:10.3390/vaccines10121993 · Cited by 67 · see citing works
Aging, cancer, and antitumor immunity
Ikeda, H., & Togashi, Y. (2021) · International Journal of Clinical Oncology · doi:10.1007/s10147-021-01913-z · Cited by 65 · see citing works
Immunosenescence and inflamm-ageing in COVID-19
Zinatizadeh, M. R., Zarandi, P. K., Ghiasi, M., Kooshki, H., Mohammadi, M., Amani, J., & Rezaei, N. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101818 · Cited by 62 · see citing works
Hammer, Q., Dunst, J., Christ, W., Picarazzi, F., Wendorff, M., Momayyezi, P., Huhn, O., Netskar, H., Maleki, K. T., García, M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110503 · Cited by 63 · see citing works
Senescence 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
DAMPs in immunosenescence and cancer
Chen, F., Tang, H., Cai, X., Lin, J., Kang, R., Tang, D., & Liu, J. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.09.005 · Cited by 59 · see citing works
Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma
Zhuang, L., Fulton, R., Rettman, P., Sayan, E., Coad, J., Al‐Shamkhani, A., & Khakoo, S. I. (2018) · Hepatology International · doi:10.1007/s12072-018-9909-3 · Cited by 55 · see citing works
Single-cell sequencing reveals antitumor characteristics of intratumoral immune cells in old mice
Zhang, C., Lei, L., Yang, X., Ma, K., Zheng, H., Su, Y., Jiao, A., Wang, X., Liu, H., Zou, Y., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002809 · Cited by 48 · see citing works
Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions
Shen, W., He, J., Hou, T., Si, J., & Chen, S. (2022) · Aging and Disease · doi:10.14336/ad.2021.1208 · Cited by 45 · see citing works
Cellular senescence in cancer: molecular mechanisms and therapeutic targets
Jin, P., Duan, X., Li, L., Zhou, P., Zou, C., & Xie, K. (2024) · MedComm · doi:10.1002/mco2.542 · Cited by 46 · see citing works
Muntasell, A., Servitja, S., Cabo, M., Bermejo, B., Pérez‐Buira, S., Rojo, F., Costa-García, M., Arpí, O., Moraru, M., Serrano, L., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0896 · Cited by 40 · see citing works
Natural killer cells in aging and age-related diseases
Qi, C., & Liu, Q. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106156 · Cited by 38 · see citing works
Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors
Hou, C., Wang, Z., & Lu, X. (2023) · Cancer Pathogenesis and Therapy · doi:10.1016/j.cpt.2023.08.001 · 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
Cutaneous Metastasis after Surgery, Injury, Lymphadenopathy, and Peritonitis: Possible Mechanisms
Otsuka, I. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133286 · Cited by 35 · see citing works
Therapeutic Development of Immune Checkpoint Inhibitors
Wang, J., Yang, T., & Xu, J. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-3266-5_23 · Cited by 34 · see citing works
Age at diagnosis is a heterogeneous factor for non-small cell lung cancer patients
Chen, T., Zhou, F., Jiang, W., Mao, R., Zheng, H. W., Qin, L., & Chen, C. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.06.24 · Cited by 33 · see citing works
Immune aging and infectious diseases
Chen, R., Zou, J., Chen, J., Wang, L., Kang, R., & Tang, D. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003410 · Cited by 33 · see citing works
Tumor Microenvironment and Nitric Oxide: Concepts and Mechanisms
Vedenko, A., Panara, K., Goldstein, G., Ramasamy, R., & Arora, H. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-50224-9_10 · Cited by 30 · see citing works
Lu, J., Li, S., Li, X., Zhao, W., Duan, X., Gu, X., Xu, J., Yu, B., Sigal, L. J., Dong, Z., et al. (2021) · Aging Cell · doi:10.1111/acel.13353 · Cited by 33 · see citing works
Systemic immune response in young and elderly patients after traumatic brain injury
Magatti, M., Pischiutta, F., Ortolano, F., Pasotti, A., Caruso, E., Cargnoni, A., Papait, A., Capuzzi, F., Zoerle, T., Carbonara, M., et al. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00369-1 · Cited by 29 · see citing works
Immune senescence and periodontitis: From mechanism to therapy
Liu, J., Dan, R., Zhou, X., Wang, J., Wang, J., & Liu, J. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0822-645rr · Cited by 23 · see citing works
Elderly-onset rheumatoid arthritis vs. polymyalgia rheumatica: Differences in pathogenesis
Wu, J., Yang, F., Ma, X., Lin, J., & Chen, W. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2022.1083879 · Cited by 24 · see citing works
Circulating innate lymphoid cells (cILCs): Unconventional lymphocytes with hidden talents
Bennstein, S. B., & Uhrberg, M. (2024) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2024.06.016 · Cited by 22 · see citing works
Self-citationGut microbiota and immunosenescence in cancer
Xu, Y., He, C., Xi, Y., Zhang, Y., & Bai, Y. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.07.004 · Cited by 22 · see citing works
Immunosenescence: A new direction in anti-aging research
Li, H., Lin, S., Wang, Y., Shi, Y., Fang, X., Wang, J., Cui, H., Bian, Y., & Qi, X. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112900 · Cited by 21 · see citing works
The Role of Targeted Agents and Immunotherapy in Older Patients with Non-small Cell Lung Cancer
Gomes, F., Tay, R. Y., Chiramel, J., & Califano, R. (2018) · Drugs & Aging · doi:10.1007/s40266-018-0573-z · Cited by 21 · see citing works
Immune response to COVID-19 in older adults
Jergović, M., Coplen, C. P., Uhrlaub, J. L., & Nikolich‐Žugich, J. (2021) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2021.04.017 · Cited by 20 · see citing works
Immunological and clinical implications of immune checkpoint blockade in human cancer
Kim, H., & Park, S. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01140-1 · Cited by 20 · see citing works
Immunotherapy for older patients with melanoma: From darkness to light?
Iacono, D., Vitale, M. G., Basile, D., Pelizzari, G., Cinausero, M., Poletto, E., Pascoletti, G., & Minisini, A. M. (2020) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12917 · Cited by 20 · see citing works
Houldcroft, C. J., Jackson, S. E., Lim, E. Y., Sedikides, G. X., Davies, E. L., Atkinson, C. E., McIntosh, M., Remmerswaal, E. B. M., Okecha, G., Bemelman, F. J., et al. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00275 · Cited by 19 · see citing works
Hasan, M. Z., Claus, M., Krüger, N., Reusing, S. B., Gall, E., Bade‐Doeding, C., Braun, A. C., Watzl, C., Uhrberg, M., & Walter, L. (2024) · Emerging Microbes & Infections · doi:10.1080/22221751.2024.2361019 · Cited by 18 · see citing works
Self-citationFrom infection to immune exhaustion: The Epstein-Barr virus and its contribution to Immunosenescence
Hu, L., Zhu, T., Long, J., Luo, Q., & Lyu, X. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189421 · Cited by 19 · see citing works
Har-Noy, M., & Or, R. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02363-3 · Cited by 20 · see citing works
Immunity to acute virus infections with advanced age
Nikolich‐Žugich, J., Bradshaw, C. M., Uhrlaub, J. L., & Watanabe, M. (2020) · Current Opinion in Virology · doi:10.1016/j.coviro.2020.09.007 · Cited by 17 · see citing works
Jinna, N., Rida, P. C. G., Su, T., Gong, Z., Yao, S., LaBarge, M. A., Natarajan, R. D., Jovanović‐Talisman, T., Ambrosone, C. B., & Seewaldt, V. L. (2022) · Cells · doi:10.3390/cells11233818 · Cited by 18 · see citing works
Seheult, J. N., Otteson, G. E., Jevremović, D., Horna, P., Timm, M., Ji, Y., Morice, W. G., Olteanu, H., & Shi, M. (2023) · Modern Pathology · doi:10.1016/j.modpat.2023.100255 · Cited by 17 · see citing works
The inter-link of ageing, cancer and immunity: findings from real-world retrospective study
Fu, X., Qin, P., Li, F., Zhu, H., You, H., Zhang, Y., Xu, B., Li, T., Zhang, F., Han, L., et al. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00399-9 · Cited by 18 · see citing works
Decoding 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
Natural killer cells, ageing and cancer
Naumova, E. J., Pawelec, G., & Mihaylova, A. (2016) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-016-1817-6 · Cited by 17 · see citing works
NK Cell Senescence in Cancer: From Molecular Mechanisms to Therapeutic Opportunities
Qiu, Z., Li, Z., Zhang, C., Zhao, Q., Liu, Z., Cheng, Q., Zhang, J., Lin, A., & Luo, P. (2025) · Aging and Disease · doi:10.14336/ad.2025.0053 · Cited by 18 · see citing works
Roma, S., Carpen, L., Raveane, A., & Bertolini, F. (2021) · Cancers · doi:10.3390/cancers13205042 · Cited by 16 · see citing works
Natural Killer Cell Diversity in Viral Infection: Why and How Much?
Blish, C. A. (2016) · Pathogens and Immunity · doi:10.20411/pai.v1i1.142 · Cited by 15 · see citing works
Immune Remodeling during Aging and the Clinical Significance of Immunonutrition in Healthy Aging
Dou, L., Yang, P., Zhang, B., Yang, H., & Zheng, K. (2023) · Aging and Disease · doi:10.14336/ad.2023.0923 · Cited by 14 · see citing works
Development of the adaptive NK cell response to human cytomegalovirus in the context of aging
López‐Botet, M., Muntasell, A., Rodríguez, J., López‐Montañés, M., Costa-García, M., & Pupuleku, A. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.06.010 · Cited by 14 · see citing works
Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation
Furlano, P. L., Böhmig, G. A., Puchhammer‐Stöckl, E., & Vietzen, H. (2024) · Transplantation · doi:10.1097/tp.0000000000004919 · Cited by 13 · see citing works
Photoactivatable Exosenolytics Activate Natural Killer Cells for Delaying Osteoarthritis
Zhang, L., Xiang, K., Li, J., Hao, M., Zhu, Z., Wang, S., & Sun, H. (2025) · ACS Nano · doi:10.1021/acsnano.5c03344 · Cited by 12 · see citing works
Cuadrado-Torroglosa, I., Pacheco, A., Barrio, A., Garrido, N., Aparicio, P., Pellicer, N., García-Velasco, J. A., & Alecsandru, D. (2023) · Fertility and Sterility · doi:10.1016/j.fertnstert.2023.02.024 · Cited by 11 · see citing works
Kołtan, S., Dębski, R., Kołtan, A., Grześk, E., Tejza, B., Eljaszewicz, A., Gackowska, L., Kubicka, M., Kołodziej, B., Kuryło-Rafińska, B., et al. (2015) · Medicine · doi:10.1097/md.0000000000002369 · Cited by 10 · see citing works
Study of calcitriol anti-aging effects on human natural killer cells in vitro
Li, W., Che, X., Chen, X., Zhou, M., Luo, X., & Liu, T. (2021) · Bioengineered · doi:10.1080/21655979.2021.1972076 · Cited by 10 · see citing works
Immunosenescence and organoids: pathophysiology and therapeutic opportunities
Kamroo, A., Kakroudi, M. H., Sarmadian, A. J., Firouzabadi, A., Mousavi, S., Yazdanpanah, N., Saleki, K., & Rezaei, N. (2025) · Immunity & Ageing · doi:10.1186/s12979-025-00530-y · Cited by 9 · see citing works
Bertoni, G., Ristori, S., & Monti, D. (2026) · Cells · doi:10.3390/cells15080657 · Cited by 9 · see citing works
Nikolich‐Žugich, J., & Davies, J. S. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12920 · Cited by 9 · see citing works
Greppi, M., Obino, V., Goda, R., Rebaudi, F., Carlomagno, S., Chiesa, M. D., Sivori, S., Ubezio, G., Agostini, V. W., Bò, A., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1183215 · Cited by 8 · see citing works
Cancer chemoresistance and therapeutic strategies targeting tumor microenvironment
Palliyage, G. H., Ghosh, R., & Rojanasakul, Y. (2020) · ScienceAsia · doi:10.2306/scienceasia1513-1874.2020.092 · Cited by 8 · see citing works
Zanwar, S., Jacob, E. K., Greiner, C. W., Pavelko, K. D., Strausbauch, M. A., Anderson, E., Arsana, A., Weivoda, M. M., Shah, M. V., & Kourelis, T. (2023) · Blood Cancer Journal · doi:10.1038/s41408-023-00920-9 · Cited by 8 · see citing works
A human NK cell progenitor that originates in the thymus and generates KIR + NKG2A − NK cells
Reiß, J., Ghosh, S., Scheid, M., Graafen, L., Scherenschlich, N., Weinhold, S., Raba, K., Paulusch, S., Domenico, E. D., Pham, T. X. U., et al. (2025) · Science Advances · doi:10.1126/sciadv.adv9650 · Cited by 7 · see citing works
Self-citationPhenotypes, mechanisms, and therapeutic strategies of natural killer cell immunosenescence
Guo, Z., Wu, F., Chen, Y., Xu, J. M., & Chen, Z. (2025) · Immunity & Ageing · doi:10.1186/s12979-025-00534-8 · Cited by 7 · see citing works
Desimio, M. G., Covino, D. A., Cancrini, C., & Doria, M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1467304 · Cited by 7 · see citing works
Tao, S., He, Y., Dong, L., He, J., Chen, N., Wang, W., Han, Z., Zhang, W., He, J., & Zhu, F. (2017) · Human Immunology · doi:10.1016/j.humimm.2017.01.005 · Cited by 7 · see citing works
Sanctis, J. B. D., Dumut, D. C., Radzioch, D., & Hajdúch, M. (2020) · Nutrients · doi:10.3390/nu12123641 · Cited by 7 · see citing works
Senescent Polarization of Macrophages and Inflammatory Biomarkers in Cardiovascular Disease
Ihan, A. (2025) · Cells · doi:10.3390/cells14171374 · Cited by 6 · see citing works
Cytomegalovirus at the crossroads of immunosenescence and oncogenesis
Bouezzedine, F., Baba, R. E., Morot-Bizot, S., Diab‐Assaf, M., & Herbein, G. (2023) · Exploration of Immunology · doi:10.37349/ei.2023.00086 · Cited by 6 · see citing works
Zhang, Y., Chu, J., Hou, Q., Qian, S., Wang, Z., Yang, Q., Song, W., Dong, L., Shi, Z., Gao, Y., et al. (2024) · International Journal of Oncology · doi:10.3892/ijo.2024.5653 · Cited by 6 · see citing works
Pagliuca, S., & Ferraro, F. (2024) · Seminars in Hematology · doi:10.1053/j.seminhematol.2024.01.002 · Cited by 6 · see citing works
Current Concepts in Natural Killer Cell Biology and Application to Drug Safety Assessments
Goyos, A., Fort, M. M., Sharma, A. M., & Lebrec, H. N. (2019) · Toxicological Sciences · doi:10.1093/toxsci/kfz098 · Cited by 6 · see citing works
The aging immune system: Dysregulation, compensatory mechanisms, and prospects for intervention
Müller, L., & Pawelec, G. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815962-0.00016-0 · Cited by 5 · see citing works
Cellular senescence: mechanisms and clinical implications
Михайловна, М. А., Pashenkov, M. V., & Pinegin, B. V. (2024) · Immunologiya · doi:10.33029/1816-2134-2024-45-2-221-234 · Cited by 10 · see citing works
Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses.
Maldini, C., Coholan, L. J., & Karaca, C. (2024) · Journal of Immunology · doi:10.4049/jimmunol.2400491 · Cited by 5 · see citing works
Immunosenescence and Cancer Immunotherapy at Old Age: Basics
Fülöp, T., Witkowski, J. M., Hirokawa, K., Larbi, A., & Pawelec, G. (2018) · Springer eBooks · doi:10.1007/978-3-319-44870-1_77-1 · Cited by 4 · see citing works
Immunosenescence and Cancer Immunotherapy at Old Age: Basics
Fülöp, T., Witkowski, J. M., Hirokawa, K., Larbi, A., & Pawelec, G. (2020) · Springer eBooks · doi:10.1007/978-3-319-57415-8_77 · Cited by 4 · see citing works
Cellular Senescence in Cancer: Mechanisms, Roles in Tumor Progression, and Therapeutic Implications
Yan, J., Zhang, Y., Mao, G., Yu, J., Zhou, T., & Hao, J. (2025) · MedComm – Oncology · doi:10.1002/mog2.70029 · Cited by 3 · see citing works
Riva, E., Carboni, S., Berardino-Besson, W. D., Moyat, M., Belnoue, E., Devy-Dimanche, L., & Rossi, M. (2024) · Cancers · doi:10.3390/cancers16112036 · Cited by 3 · see citing works
Tavakoli, S., Salavatipour, M. S., Abdolahi, S., Verdi, J., Seyhoun, I., Vosoughi, N., Vaezi, M., Ghaderi, A., Ghavamzadeh, A., Barkhordar, M., et al. (2024) · Advanced Pharmaceutical Bulletin · doi:10.34172/apb.43869 · Cited by 3 · see citing works
Hassan, F. F. A., Hamdan, M. B., & Melhem, N. M. (2019) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2019.0134 · Cited by 4 · see citing works
Shen, P., Cui, W., Lin, J., Wang, Z., Li, Z., & Liu, B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1716230 · Cited by 2 · see citing works
- Authors
- Manser, A. R., & Uhrberg, M.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Uhrberg, Markus
- ORCID
- Uhrberg, Markus
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2015-08-19
- Volume
- 65
- Issue
- 4
- Pages
- 417-426
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- PMC
- PMC11028690
- OpenAlex
- W1837057295
- Cited by
- 148
- References
- 56
- Citations by year
- 2026: 19 · 2025: 14 · 2024: 28 · 2023: 19 · 2022: 10 · 2021: 15 · 2020: 12 · 2019: 9 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 1
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Immunology Immunotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Krebshilfe (DE) (110351)
- Deutsche Forschungsgemeinschaft (DE) (UH 91/7-1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- natural killer cells, NK cell repertoire, aging, killer cell immunoglobulin-like receptors, NKG2A, NKG2C, HCMV infection, myelodysplastic syndrome, ineffective hematopoiesis, immune surveillance, healthy aging, clonal expansion
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Aging, Child, Child, Preschool, Humans, Immunologic Surveillance, Infant, Infant, Newborn, Killer Cells, Natural, Middle Aged, Myelodysplastic Syndromes, Receptors, Natural Killer Cell
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
