Evidence of premature immune aging in patients thymectomized during early childhood
Open accessAbstract
While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.
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Studies of young thymectomy subjects showed that reduced thymic function and lower production of naïve T cells, together with consumption of these cells, lead to reduced numbers of naïve T cells.
“These studies showed that, independently from age, reduced thymic function and lower production of naïve T cells, together with the consumption of these cells (e.g., upon activation and differentiation during a viral infection), lead to reduced numbers of naïve T cells [75,76].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [75]
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“Recent striking evidence from young adults thymectomized as infants in the course of cardiac surgery who have decreased naïve T cell counts further emphasizes the role of the thymus for the maintenance of the naïve T cell repertoire [17, 18].”
BackgroundSelf-citationSuessmuth, Y., Mukherjee, R., Watkins, B. K., Koura, D. T., Finstermeier, K., Desmarais, C., Stempora, L., Horan, J., Langston, A. A., Qayed, M. D., et al. (2015) · Blood · doi:10.1182/blood-2015-03-631853 · Cited by 170 · see citing works
“Moreover, a previous studyofyoung adults, thymectomized as children, showed that the combination of the lack of thymic function and CMV infection lead to dramatic changes in T-cell homeostasis.(55) These data suggest the novel hypothesis that CMV-associated thymic damagemay be one of the contributorymechanisms for the…”
BackgroundAppay, V., Fastenackels, S., Katlama, C., Aït-Mohand, H., Schneider, L., Guihot, A., Keller, M., Grubeck‐Loebenstein, B., Simon, A., Lambotte, O., et al. (2011) · AIDS · doi:10.1097/qad.0b013e32834640e6 · Cited by 167 · see citing works
“due to thymectomy early after birth) [24].”
ResultSelf-citationDeeks, S. G., Verdin, E. M., & McCune, J. M. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.05.004 · Cited by 158 · see citing works
“Thymus involution is a prominent manifestation of aging of the immune system and leads to decreased production of T cells [11].”
BackgroundImmunosenescence: Aging and Immune System Decline
Goyani, P., Christodoulou, R. C., & Vassiliou, E. K. (2024) · Vaccines · doi:10.3390/vaccines12121314 · Cited by 177 · see citing works
Age-related changes in CD8 T cell homeostasis and immunity to infection
Nikolich‐Žugich, J., Li, G., Uhrlaub, J. L., Renkema, K. R., & Smithey, M. J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.009 · Cited by 153 · see citing works
Shaping Variation in the Human Immune System
Liston, A., Carr, E. J., & Linterman, M. A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.08.002 · Cited by 145 · see citing works
. Persistent viral infections and immune aging.
Brunner, S., Herndler-Brandstetter, D., Weinberger, B., & Grubeck-Loebenstein, B. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.08.003 · Cited by 143 · see citing works
CD28 Negative T Cells: Is Their Loss Our Gain?
Mou, D., Espinosa, J. R., Lo, D. J., & Kirk, A. D. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12937 · Cited by 137 · see citing works
“Young adults who have been thymectomized during early childhood for life-saving heart surgery exhibit a T cell profile that is strongly skewed toward oligoclonal memory cells (15).”
BackgroundThe Aging Immune System and Its Relationship with Cancer
Foster, A. D., Sivarapatna, A., & Gress, R. E. (2011) · Aging Health · doi:10.2217/ahe.11.56 · Cited by 136 · see citing works
“In humans, a study on individuals thymectomized at an early age demonstrates the early onset of age-associated immune defects described as ‘premature immune aging’ [48].”
BackgroundContinuous immunotypes describe human immune variation and predict diverse responses
Kaczorowski, K. J., Shekhar, K., Nkulikiyimfura, D., Dekker, C. L., Maecker, H. T., Davis, M. M., Chakraborty, A. K., & Brodin, P. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705065114 · Cited by 136 · see citing works
de Bourcy, C. F. A., Angel, C. J. L., Vollmers, C., Dekker, C. L., Davis, M. M., & Quake, S. R. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1617959114 · Cited by 127 · see citing works
“This finding is reminiscent of results regarding relative numbers of memory T cells compared with naive T cells that have suggested CMV infection induces premature immune aging (34, 35).”
ResultA Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia
Bilbo, S. D., Smith, S. H., & Schwarz, J. M. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9299-y · Cited by 127 · see citing works
“…recognition that immune molecules are necessary for neural development and life-long function provides a plethora of novel targets within the immune system, and has recently (Wang et al. 2007) and should continue to lead to innovative and effective treatments for a wide number of neural disorders.”
BackgroundThe hallmarks of CMV-specific CD8 T-cell differentiation
van den Berg, S. P. H., Pardieck, I. N., Lanfermeijer, J., Sauce, D., Klenerman, P., van Baarle, D., & Arens, R. (2019) · Medical Microbiology and Immunology · doi:10.1007/s00430-019-00608-7 · Cited by 119 · see citing works
Self-citationPhysiology and pathology of T-cell aging
Minato, N., Hattori, M., & Hamazaki, Y. (2020) · International Immunology · doi:10.1093/intimm/dxaa006 · Cited by 121 · see citing works
“The accelerated SA-T cell generation by extensive HP in mice may be consistent with the observation of premature T-cell aging in thymectomized human patients (36).”
ResultImmunosenescence in vertebrates and invertebrates
Müller, L., Fülöp, T., & Pawelec, G. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-12 · Cited by 117 · see citing works
“In this context, neonatal thymectomy (Figure 10) for cardiac surgery and the consequent decrease in numbers of naïve cells as well as other changes seen later in life [38] would be expected to have negative health consequences too, as has been argued, but again, there is little hard evidence for this so far.”
Naive T cells: The crux of cellular immune aging?
Appay, V., & Sauce, D. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.003 · Cited by 118 · see citing works
Self-citationMoro‐García, M. A., Alonso‐Arias, R., BALTADJIEVA, M., Benítez, C. F., Barrial, M. A. F., Ruisánchez, E. D., Santos, R. A., Sánchez, M. Á., Miján, J. S., & López‐Larrea, C. (2012) · AGE · doi:10.1007/s11357-012-9434-6 · Cited by 114 · see citing works
“Elderly donors display a decline in numbers of naïve T cells in peripheral blood and lymphoid tissues (Fagnoni et al. 2000; Sauce et al. 2009); in contrast, they have a marked increase in the proportion of highly differentiated effector and memory T cells like the CD28 T cells (Goronzy et al.”
BackgroundThymic fatness and approaches to enhance thymopoietic fitness in aging
Dixit, V. D. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.06.010 · Cited by 112 · see citing works
“The peripheral T cell repertoire of 22-year old thymectomized patients is similar to that of 75-year old subjects (1).”
BackgroundResultIs immunosenescence influenced by our lifetime “dose” of exercise?
Turner, J. E. (2016) · Biogerontology · doi:10.1007/s10522-016-9642-z · Cited by 112 · see citing works
Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection
Freeman, M. L., Lederman, M. M., & Gianella, S. (2016) · Current HIV/AIDS Reports · doi:10.1007/s11904-016-0297-9 · Cited by 112 · see citing works
CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Sato, Y., Oguchi, A., Fukushima, Y., Masuda, K., Toriu, N., Taniguchi, K., Yoshikawa, T., Cui, X., Kondo, M., Hosoi, T., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146071 · Cited by 112 · see citing works
“adult stage leads to accelerated SAT cell generation (17), which is consistent with the observation that T cell aging is accelerated in thymectomized human patients (18) and suggests SAT development is involved in T cell proliferation.”
ResultNeonatal thymectomy reveals differentiation and plasticity within human naive T cells
van den Broek, T., Delemarre, E. M., Janssen, W. J. M., Nievelstein, R. A. J., Broen, J. C., Tesselaar, K., Borghans, J. A. M., Nieuwenhuis, E. E. S., Prakken, B. J., Mokry, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84997 · Cited by 104 · see citing works
“Furthermore, following neonatal thymectomy, the T cell compartment composition and phenotype resemble those of an adult, which has been regarded as premature immune aging (20).”
BackgroundInfluentialYu, M., Li, G., Lee, W.-W., Yuan, M., Cui, D., Weyand, C. M., & Goronzy, J. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109797109 · Cited by 102 · see citing works
Tolerance has its limits: how the thymus copes with infection
Nunes-Alves, C., Nóbrega, C., Behar, S. M., & Correia‐Neves, M. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.06.004 · Cited by 102 · see citing works
Lymphocyte generation and population homeostasis throughout life
Yanes, R. E., Gustafson, C. E., Weyand, C. M., & Goronzy, J. J. (2016) · Seminars in Hematology · doi:10.1053/j.seminhematol.2016.10.003 · Cited by 100 · see citing works
“cell population changes associated with immune aging [8].”
BackgroundOvercoming immune dysfunction in the elderly: trained immunity as a novel approach
Bulut, O., Kilic, G., Domínguez-Andrés, J., & Netea, M. G. (2020) · International Immunology · doi:10.1093/intimm/dxaa052 · Cited by 99 · see citing works
“People who had undergone thymectomy in early childhood show a premature immunosenescent phenotype (83).”
BackgroundImmune Senescence: Relative Contributions of Age and Cytomegalovirus Infection
Mekker, A., Tchang, V. S., Haeberli, L., Oxenius, A., Trkola, A., & Karrer, U. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002850 · Cited by 98 · see citing works
“Indeed, several human studies have shown that naı̈ve CD8 T cell frequencies in the blood were significantly reduced in HCMVinfected elderly or thymectomised young adults [26,28,46] but only few studies have reported significant reductions of absolute naı̈ve CD8 T cell numbers [27].”
BackgroundEvidence for a stepwise program of extrathymic T cell development within the human tonsil
McClory, S., Hughes, T. L., Freud, A. G., Briercheck, E. L., Martin, C. K., Trimboli, A. J., Yu, J., Zhang, X., Leone, G. W., Nuovo, G. J., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci46125 · Cited by 94 · see citing works
“For example, T cell deficiency is characteristic in patients with poor thymic function due to complete DiGeorge syndrome, chemoablation or radioablation, or surgical thymectomy (48–52).”
Elyahu, Y., & Monsonego, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101231 · Cited by 91 · see citing works
Molecular Mechanisms Involved in the Aging of the T-cell Immune Response
Moro‐García, M. A., Alonso‐Arias, R., & López‐Larrea, C. (2012) · Current Genomics · doi:10.2174/138920212803759749 · Cited by 85 · see citing works
The impact of aging on memory T cell phenotype and function in the human bone marrow
Herndler‐Brandstetter, D., Landgraf, K., Tzankov, A., Jenewein, B., Brunauer, R., Laschober, G. T., Parson, W., Kloss, F. R., Gassner, R. J., Lepperdinger, G., et al. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.0611299 · Cited by 88 · see citing works
“As a consequence, the number of total CD8 T cells in the PB, spleen, and LNs of elderly persons decreases during aging [5, 6, 44, 45].”
BackgroundSelf-citationEvaluating Cellular Polyfunctionality with a Novel Polyfunctionality Index
Larsen, M., Sauce, D., Arnaud, L., Fastenackels, S., Appay, V., & Gorochov, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042403 · Cited by 86 · see citing works
“[38] The methodologies behind the datasets are therefore only briefly described here.”
Self-citationLymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults
Sauce, D., Larsen, M., Fastenackels, S., Roux, A., Gorochov, G., Katlama, C., Sidi, D., Sibony-Prat, J., & Appay, V. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201235 · Cited by 82 · see citing works
“Young adults thymectomized during early childhood (YATEC) can also exhibit very similar characteristics, as a result of the poor thymic activity eventually affecting the size of the naive T cell pool (3, 4).”
BackgroundSelf-citationHost Resistance and Immune Aging
Bandaranayake, T., & Shaw, A. C. (2016) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2016.02.007 · Cited by 85 · see citing works
CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Sato, Y., Oguchi, A., Fukushima, Y., Masuda, K., Toriu, N., Taniguchi, K., Yoshikawa, T., Cui, X., Kondo, M., Hosoi, T., et al. (2022) · Institutional Repositories DataBase (IRDB) · Cited by 82 · see citing works
Qi, Q., Zhang, D. W., Weyand, C. M., & Goronzy, J. J. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.005 · Cited by 79 · see citing works
“…notion, thymectomyduring early childhood caused changes in T cell population similar to those in the elderly, such as reduced CD4 and CD8 T cell numbers, in particular of naïve T cells (Halnon et al., 2005; Prelog et al., 2009; Sauce et al., 2009; van Gent et al., 2011; Zlamy and Prelog, 2009).”
BackgroundResultNKG2D expression in CD4+ T lymphocytes as a marker of senescence in the aged immune system
Alonso‐Arias, R., Moro‐García, M. A., López‐Vázquez, A., Rodrigo, L., Baltar, J., García, F. M. S., Jaurrieta, J. J. S., & López‐Larrea, C. (2011) · AGE · doi:10.1007/s11357-010-9200-6 · Cited by 76 · see citing works
“Thymic involution implies a decreased output of naïve T cells, which is evident in peripheral blood and the lymph nodes (Fagnoni et al. 2000; Sauce et al. 2009; Appay et al. 2010).”
BackgroundThe impact of age-related syndromes on ICU process and outcomes in very old patients
Vallet, H., Guidet, B., Boumendil, A., de Lange, D. W., Leaver, S. K., Szczeklik, W., Jung, C., Sviri, S., Beil, M., & Flaatten, H. K. (2023) · Annals of Intensive Care · doi:10.1186/s13613-023-01160-7 · Cited by 75 · see citing works
“the decrease of naive T cells number due to thymic involution [12]; 2.”
BackgroundMechanisms of immunosenescence: lessons from models of accelerated immune aging
Saux, S. L., Weyand, C. M., & Goronzy, J. J. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06297.x · Cited by 75 · see citing works
Acquired myasthenia gravis in childhood
Evoli, A. (2010) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32833c32af · Cited by 74 · see citing works
Differential Impact of Age and Cytomegalovirus Infection on the γδ T Cell Compartment
Roux, A., Mourin, G., Larsen, M., Fastenackels, S., Urrutia, A., Gorochov, G., Autran, B., Donner, C., Sidi, D., Sibony-Prat, J., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202940 · Cited by 68 · see citing works
“In donors with suboptimal T cell renewal, CMV is directly associated with exhaustion of the naive T cell pool and the development of an immunosenescence-like phenotype (6).”
BackgroundSelf-citationBrück, O. E., Dufva, O., Hohtari, H. R., Blom, S., Turkki, R., Ilander, M. M., Kovanen, P. E., Pallaud, C., Ramos, P. M., Lähteenmäki, H., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2019000792 · Cited by 69 · see citing works
“Time from diagnosis to event,* median (range), mo 13 (0-132) 22 (5-48)”
BackgroundAssociations between Virologic and Immunologic Dynamics in Blood and in the Male Genital Tract
Gianella, S., Strain, M. C., Rought, S. E., Vargas, M. V., Little, S. J., Richman, D. D., Spina, C. A., & Smith, D. M. (2011) · Journal of Virology · doi:10.1128/jvi.06077-11 · Cited by 68 · see citing works
“Since chronic persistent immune activation negatively impacts HIV disease progression (18, 21, 24, 25, 37, 58, 70, 75) and immune activation in response to CMV may be responsible for accelerated immunosenescence (1, 23, 33, 49, 55, 63, 73, 77), CMV replication localized to the genital tract is likely a major factor in…”
Backgroundvan Gent, R., Schadenberg, A. W. L., Otto, S. A., Nievelstein, R. A. J., Sieswerda, G. T., Haas, F., Miedema, F. F., Tesselaar, K., Jansen, N. J. G., & Borghans, J. A. M. (2011) · Blood · doi:10.1182/blood-2011-03-341396 · Cited by 67 · see citing works
Mode of action of adjuvants: Implications for vaccine safety and design
Mastelic, B., Ahmed, S., Egan, W. M., Giudice, G. D., Golding, H., Gust, I. D., Neels, P., Reed, S. G., Sheets, R., Siegrist, C., et al. (2010) · Biologicals · doi:10.1016/j.biologicals.2010.06.002 · Cited by 66 · see citing works
Cytomegalovirus-Specific T Cell Immunity Is Maintained in Immunosenescent Rhesus Macaques
Čičin‐Šain, L., Sylwester, A. W., Hagen, S. I., Siess, D. C., Currier, N., Legasse, A. W., Fischer, M. B., Koudelka, C. W., Axthelm, M. K., Nikolich‐Žugich, J., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100560 · Cited by 66 · see citing works
“This innate immune resetting may have a negative effect on immune homeostasis when maintained over long periods of time and/or when associated with other pathology such as thymic involution (78).”
BackgroundCoordinated expansion of both memory T cells and NK cells in response to CMV infection in humans
Bayard, C., Lepetitcorps, H., Roux, A., Larsen, M., Fastenackels, S., Salle, V., Vieillard, V., Marchant, A., Stern, M., Boddaert, J., et al. (2016) · European Journal of Immunology · doi:10.1002/eji.201546179 · Cited by 65 · see citing works
Self-citationThe role of the thymus in immunosenescence: lessons from the study of thymectomized individuals
Appay, V., Sauce, D., & Prelog, M. (2010) · Aging · doi:10.18632/aging.100122 · Cited by 66 · see citing works
Self-citationAssessing immune aging in HIV-infected patients
Appay, V., & Sauce, D. (2016) · Virulence · doi:10.1080/21505594.2016.1195536 · Cited by 65 · see citing works
“mic output, together with their consumption upon chronic activation due to a persistent virus infection.(21,22) Interestingly, perinatally HIV-infected subjects displayed preserved na€ıve T cell counts associated with high recent”
BackgroundSelf-citationElrashdy, F., Redwan, E. M. M. M., & Uversky, V. N. (2020) · Biomolecules · doi:10.3390/biom10091312 · Cited by 64 · see citing works
Altered thymic activity in early life: how does it affect the immune system in young adults?
Sauce, D., & Appay, V. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.05.001 · Cited by 64 · see citing works
Self-citationImmunity and inflammation: the neglected key players in congenital heart disease?
Wienecke, L. M., Cohen, S., Bauersachs, J. K., Mebazaa, A., & Chousterman, B. G. (2021) · Heart Failure Reviews · doi:10.1007/s10741-021-10187-6 · Cited by 62 · see citing works
“Loss of naïve T cells and consecutive accumulation of oligoclonal memory cells was also directly associated with cytomegalovirus (CMV) infections in thymectomized ACHD [14].”
BackgroundResultInfluentialManagement of Juvenile Myasthenia Gravis
Ionita, C., & Acsádi, G. (2013) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2012.07.008 · Cited by 60 · see citing works
“There are concerns that thymectomy performed at a young age may lead to premature immunosenescence [38].”
BackgroundFali, T., Papagno, L., Bayard, C., Mouloud, Y., Boddaert, J., Sauce, D., & Appay, V. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801475 · Cited by 60 · see citing works
“infection is indeed associated with decreased proportions of naive T lymphocytes but mostly an overrepresentation of EM CD57 CD8 T cells (32, 33), EM CD57 Vd2(2) T cells (18, 34, 35), and NKG2A(2) NKG2C CD57 NK cells (20, 36–38), which are”
BackgroundSelf-citationUremia-Associated Ageing of the Thymus and Adaptive Immune Responses
Betjes, M. G. H. (2020) · Toxins · doi:10.3390/toxins12040224 · Cited by 57 · see citing works
“Of note, the decrease in naïve T cells may itself increase the expansion of memory T cells as has been shown in an experimental setting [86] and young adults after thymectomy as a child [87].”
BackgroundDAMPs 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
Bim Dictates Naive CD4 T Cell Lifespan and the Development of Age-Associated Functional Defects
Tsukamoto, H., Huston, G. E., Dibble, J. P., Duso, D. K., & Swain, S. L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001668 · Cited by 57 · see citing works
Hamazaki, Y., Sekai, M., & Minato, N. (2016) · Immunological Reviews · doi:10.1111/imr.12412 · Cited by 54 · see citing works
“Supporting these findings, humans who underwent surgical thymectomy with congenital heart disease in infancy showed significantly higher peripheral na€ıve T-cell expansion compared to in age-matched control adults and exhibit premature immune aging (149, 150).”
ResultNicoli, F., Papagno, L., Frere, J. J., Cabral-Piccin, M. P., Clave, E., Emma Gostick, D., Toubert, A., Price, D. A., Caputo, A., & Appay, V. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02736 · Cited by 55 · see citing works
“…observations hold potential biological relevance in light of previous reports showing that natural and vaccine-induced T-cells mediate protection against different pathogens as a function of differentiation (56–58) and that dysfunctional T-cells accumulate in many pathological conditions (59, 60).”
Self-citationThe Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence
Heath, J., & Grant, M. D. (2020) · Cells · doi:10.3390/cells9030766 · Cited by 56 · see citing works
“showed that this is not true for thymectomized children infected with CMV [74].”
BackgroundLitjens, N. H. R., de Wit, E. A., & Betjes, M. G. H. (2011) · Immunity & Ageing · doi:10.1186/1742-4933-8-2 · Cited by 54 · see citing works
“In addition, the changes generally observed with an aged immune system, like a decreased CD4/CD8 ratio and expansion of CD28 negative CD8 positive T cells seem to be related to CMV seropositivity [11-13].”
BackgroundAging and Options to Halt Declining Immunity to Virus Infections
Palacios-Pedrero, M. Á., Osterhaus, A. D. M. E., Becker, T., Elbahesh, H., Rimmelzwaan, G. F., & Saletti, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.681449 · Cited by 55 · see citing works
Immunological features beyond CD4/CD8 ratio values in older individuals
Garrido‐Rodríguez, V., Herrero-Fernández, I., Castro, M. J., Castillo, A., Rosado‐Sánchez, I., Galvá, M. I., Ramos, R., Olivas‐Martínez, I., Bulnes‐Ramos, Á., Cañizares, J., et al. (2021) · Aging · doi:10.18632/aging.203109 · Cited by 55 · see citing works
“It is possible that induction of CMVspecific responses would exhaust the naïve T-cell pool in the absence of adequate T-cell renewal from the thymus [28].”
BackgroundMethodAlbareda, M. C., Rissio, A. M. D., Tomás, G., Serjan, A., Alvarez, M., Viotti, R. J., Fichera, L. E., Esteva, M. I., Potente, D., Armenti, A., et al. (2013) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0002575 · Cited by 54 · see citing works
“Several studies have shown accelerated immune aging in HIVinfected subjects and subjects chronically infected with cytomegalovirus [40].”
BackgroundMoss, P. A. H. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.07.001 · Cited by 52 · see citing works
The immune system in the aging human
Rymkiewicz, P. D., Heng, Y. X., Vasudev, A., & Larbi, A. (2012) · Immunologic Research · doi:10.1007/s12026-012-8289-3 · Cited by 50 · see citing works
“In this particular clinical setting, it was demonstrated that response to CMV infection was the major cause for the exhaustion of naı̈ve T cells [107].”
BackgroundWong, G. C. L., Ng, T. K. S., Lee, J. L., Lim, P. Y., Chua, S. K. J., Tan, C. T. Y., Chua, M., Tan, J. S. H., Lee, S. M., Sia, A., et al. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa271 · Cited by 48 · see citing works
“First, thymic involution contributes to the age-dependent loss of naive T cells representation in the periphery (7).”
BackgroundThymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis
Chen, Y., Qiao, S., Tuckermann, J. P., Okret, S., & Jondal, M. (2010) · The FASEB Journal · doi:10.1096/fj.10-168724 · Cited by 49 · see citing works
Vescovini, R., Fagnoni, F. F., Telera, A. R., Bucci, L., Pedrazzoni, M., Magalini, F., Stella, A., Pasin, F., Medici, M. C., Calderaro, A., et al. (2014) · AGE · doi:10.1007/s11357-013-9594-z · Cited by 48 · see citing works
“…fewer CD8+ naïve T cells (Almanzar et al. 2005; Weinberger et al. 2007; Chidrawar et al. 2009; Derhovanessian et al. 2010, 2011; Litjens et al. 2011; Sauce et al. 2009) in comparison with uninfected subjects, but also represent the vast majority of elderly people (Boeckh and Geballe 2011; Natali…”
BackgroundResultInfluentialCD8+ T cell differentiation in the aging immune system: until the last clone standing
Buchholz, V. R., Neuenhahn, M., & Busch, D. H. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.05.002 · Cited by 46 · see citing works
Morsheimer, M. M., Rychik, J. R., Forbes, L. R., Dodds, K. M., Goldberg, D., Sullivan, K. E., & Heimall, J. R. (2016) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2015.11.034 · Cited by 46 · see citing works
Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7
Silva, S. L., Albuquerque, A. S., Serra‐Caetano, A., Foxall, R. B., Pires, A. R., Matoso, P., Fernandes, S. M., Ferreira, J., Cheynier, R., Victorino, R. M. M., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7512 · Cited by 47 · see citing works
“com/oncotarget been consistently reported, confirming the central role of the thymus [11-14].”
BackgroundResultFerrando‐Martínez, S., Lorente, R., Gurbindo, D., de José, M. I., Leal, M., Muñoz‐Fernández, M. Á., & Correa‐Rocha, R. (2014) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2013.12.013 · Cited by 44 · see citing works
“177 Neutrophils 1623 [695-3301] 2240 [942-3303] NS Monocytes 693 [421-780] 515 [266-885] NS Eosinophils 183 [51-402] 220 [75-445] NS Basophils 75 [64-84] 74 [47-107] NS B cells 793 [577-1283] 742 [454-996] NS NK cells 423 [363-784] 322 [189-589] NS NKT cells 11 [7-40] 22 [13-42] NS CD4 T cells 1003 [546-1125] 1359 [10…”
Halnon, N. J., Cooper, P., Chen, D. Y. H., Boechat, M. I., & Uíttenbogaart, C. H. (2011) · Clinical and Developmental Immunology · doi:10.1155/2011/915864 · Cited by 44 · see citing works
“Some of the long-term effects on T-cell production have been described but to date immune dysregulation has not been fully investigated in these individuals [18, 24, 34, 35].”
BackgroundImpact of stress on aged immune system compartments: Overview from fundamental to clinical data
Fali, T., Vallet, H., & Sauce, D. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.02.007 · Cited by 43 · see citing works
“T-cells Age-related changes in T cell compartment are characterized by 3 main hallmarks: (i) decrease of naïve T cells numbers related to thymic involution (Sauce et al., 2009; Zlamy et al., 2016).”
BackgroundSelf-citationEarly Thymectomy Is Associated With Long-Term Impairment of the Immune System: A Systematic Review
Cavalcanti, N. V., Palmeira, P., Jatene, M. B., Dorna, M. D. B., & Carneiro-Sampaio, M. M. S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.774780 · Cited by 44 · see citing works
“Other cytokines and chemokines were also analyzed, and the following differences in their serum levels were observed in thymectomized individuals compared to controls: (i) increased IFN-g, IL-17, IL-13, TNF-a, CXCL13, IL-8, IL-1b and eotaxin; (ii) decreased IL-8; and (iii) similar IL-21, IL-2, and IL-4 (7, 10, 20, 24).”
BackgroundResultInfluentialIL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity
Silva, S. L., Albuquerque, A. S., Matoso, P., Muylder, B. C.-D., Cheynier, R., Ligeiro, D., Abecasis, M., Anjos, R. T., Barata, J. T., Victorino, R. M. M., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00020 · Cited by 42 · see citing works
“Our molecular strategy to stringently rule out the existence of thymic output in thymectomized patients overcomes the limitations of other approaches based solely on surgical reports (21, 23, 32, 44–46) and/or thoracic imaging (21, 32, 45, 48), which may have neglected thymic regeneration or ectopic thymus (49).”
BackgroundResultInfluentialPredicting therapeutic response to fingolimod treatment in multiple sclerosis patients
Quirant‐Sánchez, B., Hervás, J. V., Teniente‐Serra, A., Brieva, L., Torres, E. M., Cano, A., Munteis, E., Mansilla, M. J., Presas‐Rodríguez, S., Navarro‐Barriuso, J., et al. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12851 · Cited by 42 · see citing works
Neonatal thymectomy in children—accelerating the immunologic clock?
Deyà‐Martínez, À., Flinn, A. M., & Gennery, A. R. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.02.028 · Cited by 41 · see citing works
- Authors
- Sauce, D., Larsen, M., Fastenackels, S., Duperrier, A., Keller, M., Grubeck-Loebenstein, B., Ferrand, C., Debré, P., Sidi, D., & Appay, V.
- Affiliations
- Inserm (FR)
- US Forest Service (US)
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Appay, Victor
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2009-10-01
- Volume
- 119
- Issue
- 10
- Pages
- 3070-3078
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2752077
- OpenAlex
- W2153680933
- Cited by
- 278
- References
- 57
- Citations by year
- 2026: 16 · 2025: 11 · 2024: 18 · 2023: 14 · 2022: 15 · 2021: 16 · 2020: 15 · 2019: 11 · 2018: 14 · 2017: 14 · 2016: 17 · 2015: 12 · 2014: 11 · 2013: 22 · 2012: 22
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Oesterreichisches Musiklexikon online (Institut für kunst- und musikhistorische Forschungen der Österreichischen Akademie der Wissenschaften) (submittedVersion, other-oa)
- Austrian Biographical Dictionary (Austrian Academy of Sciences) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- Sidaction
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- thymectomy, thymus, T cell compartment, naive T cells, cytomegalovirus infection, CMV-specific T-cell responses, T cell exhaustion, congenital heart surgery, CD4+ T cells, CD8+ T cells
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Aging, Child, Preschool, Cytomegalovirus Infections, Humans, Immune System, Infant, Newborn, Middle Aged, Thymectomy, CD4-Positive T-Lymphocytes, T-Lymphocyte Subsets, Cytokines, CD8-Positive T-Lymphocytes, Young Adult
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