Cited by 1,339Cytomegalovirus and herpesvirus researchT-cell and B-cell Immunologyvaccines and immunoinformatics approaches

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Broadly targeted human cytomegalovirus-specific CD4 + and CD8 + T cells dominate the memory compartments of exposed subjects

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Sylwester, Andrew W., Mitchell, Bridget L., Edgar, John B., Taormina, Cara, Pelte, Christian, Ruchti, Franziska, Sleath, Paul R., Grabstein, Kenneth H., Hosken, Nancy A., Kern, Florian, Nelson, Jay A., Picker, Louis J.·2005·The Journal of Experimental Medicine

DOI 10.1084/jem.20050882PMC PMC2212883

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Abstract

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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Background
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Influential
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Background
Programmed Death–1 Expression in Liver Transplant Recipients as a Prognostic Indicator of Cytomegalovirus Disease
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“Positive control pools containing CEF and CMV peptides were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: CEF control peptide pool (Cat # 9808) from DAIDS, NIAID; CMV pp65 peptide mix (Cat # 551969) from BD Biosciences.”
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Background
Extracellular Lactate: A Novel Measure of T Cell Proliferation
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“, as a read-out of CMV exposure status) (11).”
BackgroundMethod
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Background
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Method
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BackgroundResult
Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65495–503-specific CD8+ T cells in older adults
Leng, S. X., Qu, T., Semba, R. D., Li, H., Xu, Y., Nilles, T. L., Yang, X., Manwani, B., Walston, J. D., Ferrucci, L., et al. (2011) · AGE · doi:10.1007/s11357-011-9205-9 · Cited by 57
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Method
Human Cytomegalovirus: Propagation, Quantification, and Storage
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“In some normal individuals, up to 5% of circulating CD8+ T lymphocytes may be HCMV specific, raising the possibility that persistence of HCMV CD8+ in normal hosts may lead to immune senescence through chronic stimulation of the host antiviral immune response (Sylwester et al., 2005).”
Background
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Jones, M., Ladell, K., Wynn, K. K., Stacey, M. A., Quigley, M. F., Emma Gostick, D., Price, D. A., & Humphreys, I. R. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001535 · Cited by 56
“immune competent humans and mice (17, 18), a phenomenon that has been termed “memory inflation” (19).”
Background
Competition for Antigen at the Level of the APC Is a Major Determinant of Immunodominance during Memory Inflation in Murine Cytomegalovirus Infection
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“target epitopes expressed with IE, E, and L kinetics (11), and cells”
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“The containment of herpesvirus replication takes up considerable immune resources, with CMV in particular seeming to be immunodominant, becoming the primary target of 10%–30% of all circulating CD4 T lymphocytes and up to 50% of all circulating CD8 T lymphocytes in CMV infected elderly individuals [15, 16].”
Background
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“Approximately 10% of all circulating CD4+ and CD8+ T cells are involved in this process (4).”
Background
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Hakki, M. (2020) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-020-00557-6 · Cited by 55
A cytomegalovirus-based vaccine expressing a single tumor-specific CD8+ T cell epitope delays tumor growth in a murine model of prostate cancer
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Tissue‐resident T cells, in situ immunity and transplantation
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“HCMV-specific CD4 T cells are also found abundantly in circulation—up to 10% of peripheral blood memory CD4 T cells in adults (128).”
Background
Cytomegalovirus- and Epstein-Barr Virus–Induced T-Cell Expansions in Young Children Do Not Impair Naive T-cell Populations or Vaccination Responses: The Generation R Study
van den Heuvel, D., Jansen, M. A. E., Dik, W. A., Bouallouch-Charif, H., Zhao, D., van Kester, K. A. M., Nijenhuis, M. S.-T., Kolijn-Couwenberg, M. J., Jaddoe, V. W. V., Arens, R., et al. (2015) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiv369 · Cited by 54
T‐Cell Phenotypes Predictive of Frailty and Mortality in Elderly Nursing Home Residents
Johnstone, J., Parsons, R., Botelho, F. M., Millar, J., McNeil, S., Fülöp, T., McElhaney, J. E., Andrew, M. K., Walter, S. D., Devereaux, P. J., et al. (2016) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14507 · Cited by 55
“To determine T-cell reactivity to CMV, responses to CMV pp65 were tested, but T-cell reactivity is broader than to CMV pp65 alone.(41) In addition, the frailty analysis was conducted as a cross-sectional study; future study is needed to determine whether the immune biomarkers identified in the current study predict fr…”
Background
Cytomegalovirus (CMV) Epitope–Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects
Abana, C. O., Pilkinton, M. A., Gaudieri, S., Chopra, A., McDonnell, W. J., Wanjalla, C. N., Barnett, L. D., Gangula, R., Hager, C. C., Jung, D. K., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700851 · Cited by 56
Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets
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“The relative large CMV-related increase in total T cell numbers (> 30%) indicate a bystander effect on other T cells [10] which is in accordance with the discrepancy noted between e.”
BackgroundResult
Tissue maintenance of CMV-specific inflationary memory T cells by IL-15
Baumann, N. S., Torti, N., Welten, S. P. M., Barnstorf, I., Borsa, M., Pallmer, K., Oduro, J. D., Čičin-Šain, L., Ikuta, K., Ludewig, B., et al. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006993 · Cited by 53
Aging 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
Human cytomegalovirus targets different subsets of antigen‐presenting cells with pathological consequences for host immunity: implications for immunosuppression, chronic inflammation and autoimmunity
Varani, S., Frascaroli, G., Landini, M. P., & Söderberg‐Nauclér, C. (2009) · Reviews in Medical Virology · doi:10.1002/rmv.609 · Cited by 55
“Despite the functional debilitation of infected APCs, large numbers of specific effector and memory CD4þ and CD8þ T-cells develop during acute HCMV infection and help clear a productive infection [69,70].”
Background
T Cells Engineered with a Cytomegalovirus-Specific Chimeric Immunoreceptor
Full, F., Lehner, M., Thonn, V., Goetz, G., Scholz, B., Kaufmann, K. B., Mach, M., Abken, H., Holter, W., & Ensser, A. (2010) · Journal of Virology · doi:10.1128/jvi.02117-09 · Cited by 54
Cytomegalovirus infection induces T‐cell differentiation without impairing antigen‐specific responses in Gambian infants
Miles, D. J. C., Sanneh, M., Holder, B. S., Crozier, S., Nyamweya, S., Touray, E. S., Palmero, M. S., Zaman, S. M. A., Rowland‐Jones, S., van der Sande, M. A. B., et al. (2008) · Immunology · doi:10.1111/j.1365-2567.2007.02787.x · Cited by 53
CCR2 Identifies a Stable Population of Human Effector Memory CD4+ T Cells Equipped for Rapid Recall Response
Zhang, H. H., Song, K., Rabin, R. L., Hill, B. J., Perfetto, S. P., Roederer, M., Douek, D. C., Siegel, R. M., & Farber, J. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904156 · Cited by 55
Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation
Reddehase, M. J. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00294 · Cited by 54
““Immunodominant epitopes” (IDEs) differ between human individuals (56) and between different mouse strains (30, 121), reflecting MHC-I polymorphism on the host population level.”
Background
Reduced Ebola vaccine responses in CMV+ young adults is associated with expansion of CD57+KLRG1+ T cells
Bowyer, G., Sharpe, H., Venkatraman, N., Ndiaye, P. B., Wade, D., Brenner, N., Mentzer, A. J., Mair, C., Waterboer, T., Lambe, T., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20200004 · Cited by 52
Tetramer-guided epitope mapping reveals broad, individualized repertoires of tetanus toxin-specific CD4+ T cells and suggests HLA-based differences in epitope recognition
James, E. A., Bui, J. K., Berger, D., Huston, L. J., Roti, M., & Kwok, W. W. (2007) · International Immunology · doi:10.1093/intimm/dxm099 · Cited by 54
Age-associated alterations in γδ T-cells are present predominantly in individuals infected with Cytomegalovirus
Wistuba-Hamprecht, K., Frasca, D., Blomberg, B., Pawelec, G., & Derhovanessian, E. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-26 · Cited by 52
“In fact a large fraction of these cells can be specific for this single virus [13], which can lead to an accumulation of late-differentiated CD8 T-cells, recip-”
A vaccine against cytomegalovirus: how close are we?
Permar, S. R., Schleiss, M. R., & Plotkin, S. A. (2025) · Journal of Clinical Investigation · doi:10.1172/jci182317 · Cited by 53
“In total, more than 151 HCMV ORFs were immunogenic for CD4 + and/or CD8 + T cell responses (115).”
The human CMV-UL86 peptide 981–1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34–56, but lacks the capacity to induce EAE in rhesus monkeys
Brok, H., Boven, L. A., van Meurs, M., de Rosbo, N. K., Paul, A., Kap, Y. S., Jagessar, A., Hintzen, R. Q., Keir, G., Bajramovic, J. J., et al. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.10.010 · Cited by 53
Effect of Probiotic Supplement on Cytokine Levels in HIV-Infected Individuals: A Preliminary Study
Falasca, K., Vecchiet, J., Ucciferri, C., Nicola, M. D., D’Angelo, C., & Reale, M. (2015) · Nutrients · doi:10.3390/nu7105396 · Cited by 53
“The majority of HIV-infected individuals is prone to coinfection with subsequent immune activation [13].”
Background
Effector and Central Memory Poly-Functional CD4+ and CD8+ T Cells are Boosted upon ZOSTAVAX® Vaccination
Sei, J. J., Cox, K. S., Dubey, S. A., Antonello, J. M., Krah, D. L., Casimiro, D. R., & Vora, K. A. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00553 · Cited by 55
“selection of VZV antigens Naturally acquired CMV infection elicits broad and strong T cell responses with 151 out of 231 ORF being immunogenic against CD4 and/or CD8 T cells (37).”
Background
Clinical Correlation of Cytomegalovirus Infection With CMV-specific CD8+ T-cell Immune Competence Score and Lymphocyte Subsets in Solid Organ Transplant Recipients
Meesing, A., Abraham, R. S., & Razonable, R. R. (2018) · Transplantation · doi:10.1097/tp.0000000000002396 · Cited by 53
“The role of T cells in modulating the immune response to CMV has been extensively studied.(16-19) These studies highlight the clinical association between CMV disease and the numerical and functional impairment in T cells.”
Background
Generation, maintenance and tissue distribution of T cell responses to human cytomegalovirus in lytic and latent infection
Jackson, S. E., Sedikides, G. X., Okecha, G., & Wills, M. R. (2019) · Medical Microbiology and Immunology · doi:10.1007/s00430-019-00598-6 · Cited by 52
A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection
Diamond, D. J., Rosa, C. L., Chiuppesi, F., Contreras, H., Dadwal, S., Wussow, F., Bautista, S., Nakamura, R., & Zaia, J. A. (2018) · Expert Review of Vaccines · doi:10.1080/14760584.2018.1526085 · Cited by 52
“This result demonstrates that a minimal cytotoxic epitope of nine amino acids is sufficient to elicit CTL that will protect against a lethal viral infection [163].”
BackgroundInfluential
Inconsistent Responses of Cytomegalovirus‐Specific T Cells to pp65 and IE‐1 versus Infected Dendritic Cells in Organ Transplant Recipients
Lilleri, D., Zelini, P., Fornara, C., Comolli, G., & Gerna, G. (2007) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2007.01890.x · Cited by 52
“This confirms that in some subjects the HCMV-specific T-cell repertoire is directed towards other viral proteins than pp65 and IE-1, and some subjects do not generate a detectable memory T-cell pool recognizing these two immunodominant HCMV antigens (14,15,17).”
BackgroundResult
The emerging role of cytomegalovirus in driving immune senescence: a novel therapeutic opportunity for improving health in the elderly
Moss, P. A. H. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.07.001 · Cited by 52
The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis
Hart, B. A. ‘., Jagessar, S. A., Haanstra, K. G., Verschoor, E. J., Laman, J. D., & Kap, Y. S. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00145 · Cited by 52
“Cytotoxic T cells isolated from rhesus monkeys sensitized against MOG34–56 were found to proliferate ex vivo against peptide 981–1003 from the UL86 ORF-encoded major capsid protein, an immunodominant antigen of CMV (Sylwester et al., 2005).”
BackgroundInfluential
Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4 + and CD8 + T-cell responses in older adults positively correlates with response size
Chiu, Y., Lin, C.-H., Sung, B.-Y., Chuang, Y., Schneck, J. P., Kern, F., Pawelec, G., & Wang, G. C. (2016) · Scientific Reports · doi:10.1038/srep19227 · Cited by 54
Self-citation
High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage
Bolovan‐Fritts, C., Trout, R. N., & Spector, S. A. (2007) · Blood · doi:10.1182/blood-2007-03-078881 · Cited by 52
Known unknowns: how might the persistent herpesvirome shape immunity and aging?
Nikolich-Zugich, J., Goodrum, F., Knox, K., & Smithey, M. J. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.07.011 · Cited by 51
Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-γ
Mutnal, M. B., Hu, S., Little, M. R., & Lokensgard, J. R. (2011) · Journal of NeuroVirology · doi:10.1007/s13365-011-0042-5 · Cited by 51
“Infection of both mice and humans with CMV elicits broad CD8(+) T cell responses specific for an array of viral antigens (Holtappels et al. 2008; Munks et al. 2006; Sylwester et al. 2005).”
Vaccine-Induced Control of Viral Shedding following Rhesus Cytomegalovirus Challenge in Rhesus Macaques
Abel, K., Martinez, J., Yue, Y., Lacey, S. F., Wang, Z., Strelow, L. I., Dasgupta, A., Li, Z., Schmidt, K. A., Oxford, K. L., et al. (2010) · Journal of Virology · doi:10.1128/jvi.00883-10 · Cited by 51
Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses
Rocha, C. S., Hirao, L. A., Weber, M. G., Méndez‐Lagares, G., Chang, W. L. W., Jiang, G., Deere, J. D., Sparger, E. E., Roberts, J. N., Barry, P. A., et al. (2018) · Journal of Virology · doi:10.1128/jvi.00167-18 · Cited by 53
“About 10% of memory T cells are found to be CMV-specific in healthy adults with long-term subclinical CMV infection, suggesting interactions between the host immune system and the virus (7).”
Background
Enumeration of cytomegalovirus-specific interferon CD8+ and CD4+ T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection
Solano, C., Benet, I., Clari, M. Á., Nieto, J. B., de la Cámara, R., Lopez, J., Hernández‐Boluda, J. C., Remigia, M. J., Jarque, I., Calabuig, M., et al. (2008) · Haematologica · doi:10.3324/haematol.12880 · Cited by 51
“Some patients not developing active CMV infection displayed early IFNγ CD8 and CD4γ T-cell counts below the established cut-off levels, indicating that other CMV proteins may also elicit protective immune responses.(11) Of the 7 patients developing active CMV infection after the first immunological control, 5 resolved…”
Background
Differential usage of cellular niches by cytomegalovirus versus EBV- and influenza virus-specific CD8+ T cells
van Leeuwen, E. M. M., Koning, J. J., Remmerswaal, E. B. M., van Baarle, D., van Lier, R. A. W., & ten Berge, I. J. M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.8.4998 · Cited by 50
“This implies that the total response to CMV is much larger, also considering the broad immune response to CMV that has recently been described (27).”
Background
Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells
Craenenbroeck, A. H. V., Smits, E., Anguille, S., de Velde, A. V., Stein, B., Braeckman, T., Camp, K. V., Nijs, G., Ieven, M. M., Goossens, H., et al. (2014) · Transplantation · doi:10.1097/tp.0000000000000272 · Cited by 50
“In CMVseropositive recipients, CMV infection can be the result of reactivation of latent or persistent virus or superinfection with a different strain of CMV.8 In CMV-seronegative recipients, CMV disease can result from a primary infection when receiving an allograft from a CMV-seropositive donor.”
BackgroundInfluential
Inflation and Long-Term Maintenance of CD8 T Cells Responding to a Latent Herpesvirus Depend upon Establishment of Latency and Presence of Viral Antigens
Lang, A. M., Brien, J. D., & Nikolich‐Žugich, J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0801117 · Cited by 50
“This can be challenging, as illustrated in the case of the CMV, a latent -herpesvirus that elicits T cell responses unusual in strength, breadth, and complexity (2, 3).”
BackgroundMethod
Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer’s Disease
Westman, G., Berglund, D., Widén, J., Ingelsson, M., Korsgren, O., Lannfelt, L., Sehlin, D., Lidehäll, A. K., & Eriksson, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096779 · Cited by 50
Early life imprints the hierarchy of T cell clone sizes
Gaimann, M. U., Nguyen, M., Desponds, J., & Mayer, A. (2020) · eLife · doi:10.7554/elife.61639 · Cited by 50
Adoptive T-cell immunotherapy from third-party donors: characterization of donors and set up of a T-cell donor registry
Eiz‐Vesper, B., Maecker‐Kolhoff, B., & Blasczyk, R. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00410 · Cited by 49
“The majority of studies have focused on the 65 kDa matrix phosphoprotein (pp65, also known as glycoprotein 64 and UL83) and the immediate-early protein 1 (IE1) of CMV as immunodominant targets of CMV-specific T-cell responses (Solache et al., 1999; Elkington et al., 2003; Sylwester et al., 2005).”
Background
Comparisons of CD8+ T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness
Jagannathan, P., Osborne, C. M., Royce, C., Manion, M., Tilton, J., Li, L., Fischer, S., Hallahan, C., Metcalf, J., McLaughlin, M., et al. (2009) · Journal of Virology · doi:10.1128/jvi.02128-08 · Cited by 58
“Furthermore, heightened immune responses in the context of an intermittently replicating virus might relate to the overall size and tremendous complexity of CMV, which possesses a double-strand DNA genome encoding approximately 200 open reading frames for proteins greater than 80 amino acids in length (63).”
BackgroundResultInfluential
Cytomegalovirus Vaccine Strain Towne-Derived Dense Bodies Induce Broad Cellular Immune Responses and Neutralizing Antibodies That Prevent Infection of Fibroblasts and Epithelial Cells
Cayatte, C., Schneider-Ohrum, K., Wang, Z., Irrinki, A., Nguyen, N., Lu, J., Nelson, C. L., Servat, E., Gemmell, L., Citkowicz, A., et al. (2013) · Journal of Virology · doi:10.1128/jvi.01554-13 · Cited by 49
Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System
Muñoz, M. E. C., & Fuentes‐Pananá, E. M. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02521 · Cited by 49
“Similarly, about 20% of blood memory CD4 and CD8T cells are directed against HCMV in healthy carriers (Sylwester et al., 2005).”
Background
Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection
Smithey, M. J., Venturi, V., Davenport, M. P., Buntzman, A., Vincent, B. G., Frelinger, J. A., & Nikolich‐Žugich, J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719451115 · Cited by 49
“This leads to an absolute accumulation of effector T cells specific for CMV (memory inflation) (6–8), sometimes with one or a few clonal populations occupying up to 25% of the entire CD8 T cell memory pool in elderly humans (9, 10).”
Background
Naïve and memory CD8 T cell pool homeostasis in advanced aging: impact of age and of antigen-specific responses to cytomegalovirus
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
“Functional assays with intracellular cytokine staining (ICS) in antigen-activated cells (Kern et al. 2000; Sylwester et al. 2005), and flow cytometry (FCM) staining assays with peptide-MHC (pMHC) multimers (Khan et al. 2002), both provide a partial determination of the CMV-specific T cell responses.”
Method
Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial
Weathers, S.-P. S., Peñas-Prado, M., Pei, B.-L., Ling, X., Kassab, C., Banerjee, P. P., Bdiwi, M., Shaim, H., Alsuliman, A., Shanley, M., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-0176 · Cited by 48
“Seroprevalence is over 60% (1) in adults and is associated with a strikingly high fraction (10% or more) of circulating T lymphocytes targeting CMV (2).”
Background
Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study
Ramasubramanian, R., Meier, H. C. S., Vivek, S., Klopack, E. T., Crimmins, E. M., Faul, J. D., Nikolich‐Žugich, J., & Thyagarajan, B. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00290-z · Cited by 47
Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures
Rölle, A., & Olweus, J. (2009) · Apmis · doi:10.1111/j.1600-0463.2009.02449.x · Cited by 47
“overlapping peptides covering the entire HCMV genome concluded that 5% of total peripheral blood CD4 and CD8 T cells and 10% in the memory compartment recognize a surprisingly broad range of HCMV epitopes (123).”
Background
Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging
Gustafson, C. E., Qi, Q., Hutter-Saunders, J. A. L., Gupta, S., Jadhav, R. R., Newell, E. W., Maecker, H. T., Weyand, C. M., & Goronzy, J. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00692 · Cited by 51
“The late pool consisted of pp65, UL32, UL48AB, and UL55 (gB), based on previously described work (27).”
Background
Human NK Cells and Herpesviruses: Mechanisms of Recognition, Response and Adaptation
Chiesa, M. D., Maria, A. D., Muccio, L., Bozzano, F., Sivori, S., & Moretta, L. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02297 · Cited by 44
“Indeed, the magnitude of the specific T cell response during CMV clinical latency is surprisingly high, with 10–20% of CD4 and CD8 CMV-specific circulating T cells, and 5–15% of NKG2C+ memory-like NK cells during clinical latency (Guma et al., 2004; Sylwester et al., 2005).”
Background
Human Cytomegalovirus Induces Cellular and Humoral Virus-specific Immune Responses in Humanized BLT Mice
Crawford, L. B., Tempel, R., Streblow, D. N., Kreklywich, C. N., Smith, P. P., Picker, L. J., Nelson, J. A., & Caposio, P. (2017) · Scientific Reports · doi:10.1038/s41598-017-01051-5 · Cited by 47
Self-citation
Recruitment of highly cytotoxic CD8+ T cell receptors in mild SARS-CoV-2 infection
Wagner, K. I., Mateyka, L. M., Jarosch, S., Grass, V., Weber, S., Schober, K., Hammel, M., Burrell, T., Kalali, B. N., Poppert, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110214 · Cited by 47
“To decipher the specificity of the remaining IFNG cluster-derived TCRs, we stimulated TCR-engineered T cells with autologous PBMCs pulsed with SARS-CoV-2 9-mer, cytomegalovirus (CMV), and Epstein-Barr (EBV) peptide pools because of the high prevalence of CMV and EVB infection in the human population and the induced bi…”
Cytomegalovirus-Specific Regulatory and Effector T Cells Share TCR Clonality—Possible Relation to Repetitive CMV Infections
Schwele, S., Fischer, A. M., Brestrich, G., Włodarski, M. W., Wagner, L., Schmueck‐Henneresse, M., Roemhild, A., Thomas, S., Hammer, M. H., Babel, N., et al. (2011) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03842.x · Cited by 46
“Among the complex antiviral T-cell response to >150 open reading frame of CMV (4), CMV-IE-1 (immediate-early protein-1) antigen-specific CD8+ cells seem to be crucial for preventing CMV disease but do not protect from recurring/lasting CMV reactivation (5,6).”
Background
CMV‐specific T‐cell immunity, viral load, and clinical outcome in seropositive renal transplant recipients: a pilot study
Sund, F., Lidehäll, A. K., Claesson, K., Foss, A. E., Tötterman, T. H., Korsgren, O., & Eriksson, B. (2009) · Clinical Transplantation · doi:10.1111/j.1399-0012.2009.00976.x · Cited by 46
“CMV-specific T cells have been shown to vary immensely between individuals (10, 11).”
Background
CD8+ 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 49
How understanding immunology contributes to managing CMV disease in immunosuppressed patients: now and in future
Sissons, J. G. P., & Wills, M. R. (2015) · Medical Microbiology and Immunology · doi:10.1007/s00430-015-0415-0 · Cited by 46
Immunity to Cytomegalovirus in Early Life
Huygens, A., Dauby, N., Vermijlen, D., & Marchant, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00552 · Cited by 45
“A comprehensive antigen repertoire analysis indicated that CMVspecific T cells comprise on average 10% of the total CD4 and CD8 memory T cell compartments in chronically infected healthy adults (61).”
Background
A New Model for CD8+ T Cell Memory Inflation Based upon a Recombinant Adenoviral Vector
Bolinger, B., Sims, S., O’Hara, G. A., de Lara, C., Tchilian, E. Z., Firner, S., Engeler, D. S., Ludewig, B., & Klenerman, P. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202665 · Cited by 46
T-cell responses to KSHV infection: a systematic approach
Roshan, R., Labò, N., Trivett, M. T., Miley, W., Marshall, V. A., Coren, L. V., Castro, E. M. C., Perez, H., Holdridge, B., Davis, E., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.22683 · Cited by 46
“Consequently, our understanding of cellular immune responses to KSHV is rudimentary, compared to the wealth of research available for EBV and HCMV.”
BackgroundResultInfluential

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)
ORCID: Hosken, Nancy A.
Kern, Florian
Nelson, Jay A.
Picker, Louis J.
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
DOI: 10.1084/jem.20050882
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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Broadly targeted human cytomegalovirus-specific CD4 + and CD8 + T cells dominate the memory compartments of exposed subjects

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