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Broadly targeted human cytomegalovirus-specific CD4 + and CD8 + T cells dominate the memory compartments of exposed subjects
Open accessAbstract
Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.
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“Infection with CMV causes a large accumulation of virus-specific memory T cells, so that approximately 10 % of the CD4+ and CD8+ T cell pool becomes specific for this virus (Sylwester et al. 2005).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Sylwester et al. 2005
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“It is therefore currently unknown whether values such as 10 % of the CD4+ and CD8+ T cell pool being specific for CMV is above, or below, the ideal threshold (Sylwester et al. 2005).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Sylwester et al. 2005
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BackgroundInfluentialSustained CD8+ T Cell Memory Inflation after Infection with a Single-Cycle Cytomegalovirus
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“The GzmB+ T cells that we have observed in the absence of virus stimulation may represent CMV-specific CTL that have been identified within both CD4+ [30] and CD8+ subsets [31] of older adults and are sustained at high frequencies in human PBMC.”
BackgroundA replication-defective human cytomegalovirus vaccine for prevention of congenital infection
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“Third, a higher exposure of TTV to the host as represented by a higher plasma TTV level might lead to a higher expansion of TTV-specific immune cells, as described for other chronic viral infections, particularly for human cytomegalovirus [29].”
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Cytomegalovirus and polyomavirus BK posttransplant
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“In addition to overt pathologies associated with reactivation from latency, the impact of viral coexistence on our biology is ill-defined but encompasses a wide range of possibilities, including conferring protection from other microbial infections (5), contributing to the development of vascular disease (22, 53), or…”
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“It is important to note, however, that CMV lysates (prepared from lytically CMV-infected human fibroblasts) are not an all-inclusive collection of CMV antigens (30).”
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“Despite immunocompetent individuals mounting an enormous, life-long anti-HCMV CD4 and CD8 T cell response [3, 4], primary productive infection can persist for an extended period of time, with prolonged shedding of infectious virus in urine and saliva that can last for months in adults and”
BackgroundRhesus CMV: an emerging animal model for human CMV
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“However, the frequency of shedding [6], kinetics of reactivation after transplantation [7], and the high CMV-speciWc T cell response [8] suggest that active CMV replication,”
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“It has been estimated that on average, as high as 10% of the circulating CD4-positive T cells (CD4pos T cells) are CMV-specific in the latent situation.(6) The phenotype of CD4-positive CMV-specific T cells is interesting with respect to atherosclerosis, as CMV infection increases the frequency of circulating CD4-posi…”
BackgroundInfluentialPolyfunctional T Cells Accumulate in Large Human Cytomegalovirus-Specific T Cell Responses
Lachmann, R., Bajwa, M., Vita, S., Smith, H. E., Cheek, E., Akbar, A. N., & Kern, F. (2011) · Journal of Virology · doi:10.1128/jvi.00873-11 · Cited by 102
“Up to approximately 11% of CD8 T cells and 6% of CD4 T cells responded to pp65 in this cohort, which is in line with previously published data (19, 20, 45).”
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Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction
Maidji, E., Somsouk, M., Rivera, J. M., Hunt, P. W., & Stoddart, C. A. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006202 · Cited by 102
“, retinitis, colitis, and encephalitis) is rare during ART-mediated viral suppression, CMV appears to contribute to persistent immune activation and inflammation in this setting [28] and is responsible for a sizable proportion of the entire memory T-cell response [29].”
Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation
Camargo, J. F., & Komanduri, K. V. (2017) · Hematology/Oncology and Stem Cell Therapy · doi:10.1016/j.hemonc.2017.05.001 · Cited by 102
Krishna, B. A., Poole, E. L., Jackson, S. E., Smit, M. J., Wills, M. R., & Sinclair, J. H. (2017) · mBio · doi:10.1128/mbio.01754-17 · Cited by 102
Li, X., Huang, Y., Xu, Z., Zhang, R., Liu, X., Li, Y., & Mao, P. (2018) · BMC Infectious Diseases · doi:10.1186/s12879-018-3195-5 · Cited by 103
“Second, to inhibit the reactivation of CMV, as many as 10% of all peripheral CD4+ and CD8+ T cells are constantly required for immune surveillance to maintain functional latency [41] .”
Kreutzman, A. S., Ladell, K., Koechel, C., Emma Gostick, D., Ekblom, M., Stenke, L., Melo, T., Einsele, H., Porkka, K., Price, D. A., et al. (2011) · Leukemia · doi:10.1038/leu.2011.135 · Cited by 101
Jarque, M., Crespo, E., Melilli, E., Gutiérrez, A. D., Moreso, F., Guirado, L., Revuelta, I., Montero, N., Torrás, J., Riera, L., et al. (2019) · Clinical Infectious Diseases · doi:10.1093/cid/ciz1209 · Cited by 100
Peggs, K. S., Verfuerth, S., Pizzey, A. R., Chow, S. C., Thomson, K. J., & Mackinnon, S. (2009) · Clinical Infectious Diseases · doi:10.1086/648422 · Cited by 100
“This may be important given the heterogeneity of immune responses demonstrated among healthy donors because not all have responses directed toward any specific epitope [33], and these data provide a useful comparator for the next generation of studies.”
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 99
“investigated persistent pathogens, and this response regularly occupies 20% and more of the total CD8 T cell pool [19].”
BackgroundT Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy
Mehta, P. H., Fiorenza, S., Koldej, R. M., Jaworowski, A., Ritchie, D. S., & Quinn, K. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.780442 · Cited by 99
“memory T cells in seropositive individuals (82), with higher frequencies seen in older as compared to younger individuals.”
BackgroundJohnson, P. L. F., Yates, A. J., Goronzy, J. J., & Antia, R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209283110 · Cited by 94
“In addition to the forces of mutation and selection examined in this paper, these populations are affected by factors such as the shorter telomere lengths of memory cells (46), the increased frequency of cells specific for persistent latent herpes virus infections (11, 12, 18), and interconversion between naive and me…”
Buehler, J., Zeltzer, S., Reitsma, J. M., Petrucelli, A., Umashankar, M., Rak, M. A., Zagallo, P., Schroeder, J. A., Terhune, S. S., & Goodrum, F. D. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005655 · Cited by 97
“Given the commitment of T-cell immunity to CMV infection [2], CMV likely reactivates subclinically with high frequency.”
BackgroundContribution of Herpesvirus Specific CD8 T Cells to Anti-Viral T Cell Response in Humans
Sandalova, E., Laccabue, D., Boni, C., Tan, A. T., Fink, K., Ooi, E. E., Chua, R. L., Shafaeddin-Schreve, B., Ferrari, C. I., & Bertoletti, A. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001051 · Cited by 93
“The cross-reactive potential of HCMV-specific CD8 T cells is very uncommon [7] and our data do not support cross-reactive mechanisms either.”
BackgroundMattes, F. M., Vargas, A., Kopycinski, J., Hainsworth, E. G., Sweny, P., Nebbia, G., Bazeos, A., Lowdell, M. W., Klenerman, P., Phillips, R. E., et al. (2008) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2008.02191.x · Cited by 97
“The CD8 T-cell immune response to HCMV appears to be dominated by responses to the tegument protein ppUL83 and to the immediate early protein pUL123 (22,25) although recent data using peptides representing the entire HCMV proteome reveal that many proteins are targeted by the host CD8 T-cell response (26).”
BackgroundMoutaftsi, M., Bui, H., Peters, B., Sidney, J., Salek‐Ardakani, S., Oseroff, C., Pasquetto, V., Crotty, S., Croft, M., Lefkowitz, E. J., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.11.6814 · Cited by 94
“Even more comprehensive studies have been performed for other viruses (31–33), including the complex pathogen human CMV (HCMV) by using overlapping peptides spanning the entire genome (34).”
BackgroundRosa, C. L., Longmate, J., Lacey, S. F., Kaltcheva, T. I., Sharan, R., Marsano, D., Kwon, P. D., Drake, J., Williams, B., Denison, S., et al. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis107 · Cited by 96
Tsuda, Y., Caposio, P., Parkins, C. J., Botto, S., Messaoudi, I., Čičin‐Šain, L., Feldmann, H., & Jarvis, M. A. (2011) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0001275 · Cited by 96
“CMV induces high levels of T cells against both endogenous and heterologously expressed proteins [33,34,36].”
BackgroundKhan, N., Best, D., Bruton, R. K., Nayak, L., Rickinson, A. B., & Moss, P. A. H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4455 · Cited by 95
“More recently, Picker and colleagues (12) have tested pep-”
BackgroundDerhovanessian, E., Maier, A. B., Hähnel, K., McElhaney, J. E., Slagboom, E. P., & Pawelec, G. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303361 · Cited by 93
Cheung, A. K. L., Gottlieb, D. J., Plachter, B., Pepperl‐Klindworth, S., Avdic, S., Cunningham, A. L., Abendroth, A., & Slobedman, B. (2009) · Blood · doi:10.1182/blood-2008-12-197111 · Cited by 94
Olson, N. C., Doyle, M. F., Jenny, N. S., Huber, S. A., Psaty, B. M., Kronmal, R. A., & Tracy, R. P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071498 · Cited by 94
“The consequences of latent or chronic pathogen infection, characterized by reduced naive T cells and increased memory T cells, include: accumulation of antigen-specific T cells leading to restricted T cell receptor diversity and a limited capacity to mount responses against previously unencountered antigens [42]; alte…”
BackgroundResultSmithey, M. J., Li, G., Venturi, V., Davenport, M. P., & Nikolich‐Žugich, J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201867 · Cited by 93
“It is of further note that such dramatic influences on the immune system were observed in our persistently infected cohorts that showed relatively lower levels of antiviral CD8 memory inflation compared with those we and others have previously reported (9, 11).”
BackgroundResultUpdate on the current status of cytomegalovirus vaccines
Sung, H., & Schleiss, M. R. (2010) · Expert Review of Vaccines · doi:10.1586/erv.10.125 · Cited by 93
Torre‐Cisneros, J., Fariñas, M. C., Castón, J. J., Aguado, J. M., Cantisán, S., Carratalà, J., Cervera, C., Cisneros, J. M., Cordero, E., Crespo-Leiro, M. G., et al. (2011) · Enfermedades Infecciosas y Microbiología Clínica · doi:10.1016/j.eimc.2011.05.022 · Cited by 92
Humphreys, I. R., Loewendorf, A. I., Trez, C. D., Schneider, K., Benedict, C. A., Munks, M. W., Ware, C. F., & Croft, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.4.2195 · Cited by 92
“CD4 and CD8 T cells in healthy seropositive individuals (7).”
BackgroundJing, L., Haas, J., Chong, T. M., Bruckner, J. J., Dann, G. C., Dong, L., Marshak, J. O., McClurkan, C. L., Yamamoto, T. N., Bailer, S. M., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60556 · Cited by 93
“Indeed, the low magnitude of direct PBMC IFN-γ ELISPOT responses to single HSV-1 peptides in the current report contrast with the high-magnitude responses to single epitopes noted in CMV and EBV (48, 50).”
MethodResultInfluentialHuman Cytomegalovirus Tropism for Endothelial Cells: Not All Endothelial Cells Are Created Equal
Jarvis, M. A., & Nelson, J. A. (2007) · Journal of Virology · doi:10.1128/jvi.01422-06 · Cited by 93
“Consistent with this ability of the virus to replicate irrespective of host immunity, HCMV has been shown to frequently reinfect healthy HCMV-seropositive individuals, with active replication in these individuals for months to years (1, 7). Further evidence for persistent virus replication is the observation that a su…”
BackgroundSelf-citationInsights into human CD8+ T‐cell memory using the yellow fever and smallpox vaccines
Ahmed, R., & Akondy, R. S. (2011) · Immunology and Cell Biology · doi:10.1038/icb.2010.155 · Cited by 92
CMV immune evasion and manipulation of the immune system with aging
Jackson, S. E., Redeker, A., Arens, R., van Baarle, D., van den Berg, S. P. H., Benedict, C. A., Čičin‐Šain, L., Hill, A. B., & Wills, M. R. (2017) · GeroScience · doi:10.1007/s11357-017-9986-6 · Cited by 94
New therapies for human cytomegalovirus infections
Britt, W. J., & Prichard, M. N. (2018) · Antiviral Research · doi:10.1016/j.antiviral.2018.09.003 · Cited by 92
CMV-Specific TCR-Transgenic T Cells for Immunotherapy
Schub, A., Schuster, I. G., Hammerschmidt, W., & Moosmann, A. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0902233 · Cited by 91
“Healthy individuals with persistent CMV infection carry large proportions of CMV-specific CD8 and CD4 memory T cells (19, 20).”
BackgroundWestall, G. P., Mifsud, N. A., & Kotsimbos, T. C. (2008) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2008.02294.x · Cited by 91
“Individual levels of CMV immunity varied markedly between LTR, which is perhaps not unexpected given the considerable heterogeneity in levels of CMV immunity seen in immunocompetent normal subjects (10).”
BackgroundThe Sordid Affair Between Human Herpesvirus and HIV
Gianella, S., Massanella, M., Wertheim, J. O., & Smith, D. M. (2015) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiv148 · Cited by 90
Ljungman, P. T., Alain, S., Chemaly, R. F., Einsele, H., Galaverna, F., Hirsch, H. H., Sadowska‐Klasa, A., Navarro, D., Styczyński, J., & de la Cámara, R. (2025) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(25)00069-6 · Cited by 99
Waller, E. C. P., McKinney, N., Hicks, R., Carmichael, A. J., Sissons, J. G. P., & Wills, M. R. (2007) · Blood · doi:10.1182/blood-2007-07-104604 · Cited by 90
Rosa, C. L., Limaye, A. P., Krishnan, A., Longmate, J., & Diamond, D. J. (2007) · The Journal of Infectious Diseases · doi:10.1086/511307 · Cited by 90
Elyahu, Y., & Monsonego, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101231 · Cited by 93
Scheinberg, P., Melenhorst, J. J., Brenchley, J. M., Hill, B. J., Hensel, N. F., Chattopadhyay, P. K., Roederer, M., Picker, L. J., Price, D. A., Barrett, A. J., et al. (2009) · Blood · doi:10.1182/blood-2009-04-214684 · Cited by 89
Self-citationDesirability and feasibility of a vaccine against cytomegalovirus
Griffiths, P. D., Plotkin, S. A., Mocarski, E. S., Pass, R. F., Schleiss, M. R., Krause, P. R., & Bialek, S. R. (2013) · Vaccine · doi:10.1016/j.vaccine.2012.10.074 · Cited by 87
“The possession of multiple immune evasion genes gives CMV a countermeasure against many immune defence mechanisms [41,42].”
BackgroundCytomegalovirus Vaccine Development
Schleiss, M. R. (2008) · Current topics in microbiology and immunology · doi:10.1007/978-3-540-77349-8_20 · Cited by 86
“…analysis of T-cell responses to HCMV infection was recently conducted using cytokine flow cytometry in conjunction with overlapping peptides comprising 213 HCMV open reading frames: this study demonstrated that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells (Sylwester et al. 2005).”
MethodVescovini, R., Biasini, C., Telera, A. R., Basaglia, M., Stella, A., Magalini, F., Bucci, L., Monti, D., Lazzarotto, T., Monte, P. D., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902890 · Cited by 84
“memory devoted to its control in adulthood (13) and its further expansion that occurs in healthy aging (14–16).”
BackgroundFu, T., An, Z., & Wang, D. (2014) · Vaccine · doi:10.1016/j.vaccine.2014.03.057 · Cited by 85
“Many viral structural proteins, such as tegument protein pp65, are targets of host cellular immune responses [16].”
Background
Metadata
- Authors
- Sylwester, A. W., Mitchell, B. L., Edgar, J. B., Taormina, C., Pelte, C., Ruchti, F., Sleath, P. R., Grabstein, K. H., Hosken, N. A., Kern, F., Nelson, J. A., & Picker, L. J.
- Affiliations
- Oregon National Primate Research Center (US)
- Corixa Corporation (US)
- Stiftung Charité (DE)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2005-09-05
- Volume
- 202
- Issue
- 5
- Pages
- 673-685
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2212883
- OpenAlex
- W2103849595
- Cited by
- 1,339
- References
- 41
- Citations by year
- 2026: 39 · 2025: 53 · 2024: 56 · 2023: 41 · 2022: 56 · 2021: 70 · 2020: 67 · 2019: 81 · 2018: 71 · 2017: 86 · 2016: 74 · 2015: 77 · 2014: 56 · 2013: 83 · 2012: 64
- FWCI
- 38.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (RR 00163, AI21640)
- National Institute of Allergy and Infectious Diseases (R01AI047606, AI 47606, R01AI021640)
- National Center for Research Resources (P51RR000163, M01RR000334)
- Topics
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- human cytomegalovirus, CD4+ T cells, CD8+ T cells, immunodominance, seropositive individuals, viral persistence
- MeSH terms
- Adult, Cytomegalovirus Infections, Cytomegalovirus, Female, Flow Cytometry, Humans, Immunogenetics, Immunologic Memory, Male, Middle Aged, Peptides, Serologic Tests, CD4-Positive T-Lymphocytes, Open Reading Frames, CD8-Positive T-Lymphocytes
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