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.
“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
It is 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.
“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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“A new paradigm has now emerged (based primarily on the OCTO and NONA longitudinal studies conducted in Sweden), to suggest that the age-related changes observed in T cell phenotypes and functions are highly influenced by CMV leading to increased frequency in CD81 TEMRA cells, with specificity for CMV (29).”
BackgroundMethodConfronting Complexity: Real-World Immunodominance in Antiviral CD8+ T Cell Responses
Yewdell, J. W. (2006) · Immunity · doi:10.1016/j.immuni.2006.09.005 · Cited by 365 · 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
“WHAT MIGHT THEN CAUSE THESE CHANGES IN ADAPTIVE IMMUNITY WITH AGE? Recently a new paradigm emerged, mainly following these longitudinal studies, to explain the changes with age in T cell phenotypes and functions characterized by more and more differentiated CD4+ and CD8+ T cells: CMV seropositivity determines the incr…”
ResultCytomegalovirus: pathogen, paradigm, and puzzle
Boeckh, M., & Geballe, A. P. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45449 · Cited by 358 · see citing works
Cytomegalovirus infection enhances the immune response to influenza
Furman, D., Jojic, V., Sharma, S., Shen-Orr, S. S., L. Angel, C. J., Onengut-Gumuscu, S., Kidd, B. A., Maecker, H. T., Concannon, P., Dekker, C. L., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa2293 · Cited by 332 · see citing works
Manifestations of Human Cytomegalovirus Infection: Proposed Mechanisms of Acute and Chronic Disease
Britt, W. J. (2008) · Current topics in microbiology and immunology · doi:10.1007/978-3-540-77349-8_23 · Cited by 346 · see citing works
The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response
Akondy, R. S., Monson, N. D., Miller, J. D., Edupuganti, S., Teuwen, D. E., Wu, H. G., Quyyumi, F. F., Garg, S., Altman, J. D., del Rı́o, C., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803903 · Cited by 345 · see citing works
“We have also begun to understand the differences between the properties of poor and high quality memory CD8+ T cells based on their cytotoxicity, cytokine production, homeostatic turnover, and proliferative potential (6-17).”
Hunt, P. W., Martin, J. N., Sinclair, E., Epling, L., Teague, J., Jacobson, M. Z., Tracy, R. P., Corey, L., & Deeks, S. G. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir060 · Cited by 344 · see citing works
“Because asymptomatic chronic CMV infection elicits massive immune responses in HIV-uninfected individuals [20] and even higher responses in HIV-infected individuals receiving antiretroviral therapy [21], we suspect that the valganciclovirmediated reductions in T cell activation that we observed were largely mediated b…”
BackgroundCasazza, J. P., Betts, M. R., Price, D. A., Precopio, M., Ruff, L. E., Brenchley, J. M., Hill, B. J., Roederer, M., Douek, D. C., & Koup, R. A. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052246 · Cited by 338 · see citing works
Snyder, C. M., Cho, K. S., Bonnett, E. L., van Dommelen, S. L. H., SHELLAM, G. R., & Hill, A. B. (2008) · Immunity · doi:10.1016/j.immuni.2008.07.017 · Cited by 300 · see citing works
“The T cell response to CMV in humans and mice is astonishingly large, comprising up to 10% of all CD8 T cells (Gillespie et al., 2000; Karrer et al., 2003; Lang et al., 2002; Munks et al., 2006a; Sylwester et al., 2005).”
BackgroundCho, Y., Yang, C., & Chu, C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061243 · Cited by 286 · see citing works
“Several studies have shown that CMV-specific T cells constitute the major proportion of the memory T cell repertoire in patients with latent CMV infection (10–40% of the CD4+ T cell repertoire and up to 10% of the CD8+ T cell repertoire) and that the number of these CMV-specific T cells increases with age [104,105].”
BackgroundEvidence of premature immune aging in patients thymectomized during early childhood
Sauce, D., Larsen, M., Fastenackels, S., Duperrier, A., Keller, M., Grubeck-Loebenstein, B., Ferrand, C., Debré, P., Sidi, D., & Appay, V. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39269 · Cited by 278 · see citing works
“We then measured the magnitude of IFN-γ–producing pp65- or IE1-specific T cells in all YATECs in order to get a relative picture of the total frequency of CMV-specific T cells (31).”
BackgroundMethodAging of the T Cell Compartment in Mice and Humans: From No Naive Expectations to Foggy Memories
Nikolich-Žugich, J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401174 · Cited by 259 · see citing works
“CMV induces strong (56, 57) and absolute inflation of both the EM CD8 and EM CD4 subsets (40, 58, 59), likely via direct stimulation of a wide repertoire of responding T cells with its complex peptides (60).”
BackgroundKumar, D., Chernenko, S., Moussa, G., Cobas, I., Manuel, O., Preiksaitis, J. K., Venkataraman, S., & Humar, A. (2009) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2009.02618.x · Cited by 268 · see citing works
Evasion of CD8 + T Cells Is Critical for Superinfection by Cytomegalovirus
Hansen, S. G., Powers, C. J., Richards, R. M., Ventura, A. B., Ford, J. C., Siess, D. C., Jarvis, M. A., Nelson, J. A., Jarvis, M. A., Picker, L. J., et al. (2010) · Science · doi:10.1126/science.1185350 · Cited by 266 · see citing works
Self-citationHuman cytomegalovirus immunity and immune evasion
Jackson, S. E., Mason, G. M., & Wills, M. R. (2010) · Virus Research · doi:10.1016/j.virusres.2010.10.031 · Cited by 260 · see citing works
“The total CD8 T cell response to HCMV is large, an estimation of bout 10% of the peripheral CD8 memory T cells are directed against CMV determined by screening all the HCMV ORFs in multiple indiiduals, this group included young to middle aged individuals but ot old individuals (Sylwester et al., 2005).”
InfluentialOh, S. J., Lee, J. K., & Shin, O. S. (2019) · Immune Network · doi:10.4110/in.2019.19.e37 · Cited by 261 · see citing works
“In fact, previous evidences suggest that CMV-specific memory T cells gradually increase in numbers in the elderly, and in fact, 50% of the entire memory CD8+ T cell population is occupied by CMV-specific cells (71,98,99).”
Human Cytomegalovirus Drives Epigenetic Imprinting of the IFNG Locus in NKG2Chi Natural Killer Cells
Luetke-Eversloh, M. V., Hammer, Q., Durek, P., Nordström, K. J. V., Gasparoni, G., Pink, M., Hamann, A., Walter, J., Chang, H., Dong, J., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004441 · Cited by 258 · see citing works
“Similarly, clinically silent reactivation of HCMV or of other herpesviruses also stimulates HCMV-specific T cells and dramatically shapes the T cell repertoire [52,53].”
BackgroundStanton, R. J., Baluchova, K., Dargan, D. J., Cunningham, C., Sheehy, O., Seirafian, S., McSharry, B. P., Neale, M. L., Davies, J. A., Tomašec, P., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42955 · Cited by 256 · see citing works
“In support of this, when CD4+ T cell responses to HCMV were measured, RL13 was one of the top 5 most immunogenic HCMV ORFs (73).”
Four Distinct Patterns of Memory CD8 T Cell Responses to Chronic Murine Cytomegalovirus Infection
Munks, M. W., Cho, K. S., Pinto, A. K., Sierro, S. R., Klenerman, P., & Hill, A. B. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.1.450 · Cited by 254 · see citing works
“6% of CD8 T cells from seropositive adults are HCMV specific (1).”
BackgroundPrevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine
Hansen, S. G., Zak, D. E., Xu, G., Ford, J. C., Marshall, E. E., Malouli, D., Gilbride, R. M., Hughes, C. M., Ventura, A. B., Ainslie, E., et al. (2018) · Nature Medicine · doi:10.1038/nm.4473 · Cited by 244 · see citing works
Self-citationChidrawar, S. M., Khan, N., Wei, W., McLarnon, A., Smith, N., Nayak, L., & Moss, P. A. H. (2009) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2008.03785.x · Cited by 244 · see citing works
Cytomegalovirus Infection: A Driving Force in Human T Cell Immunosenescence
KOCH, S., LARBI, A., ÖZCELIK, D., SOLANA, R., GOUTTEFANGEAS, C., ATTIG, S., WIKBY, A., STRINDHALL, J., FRANCESCHI, C., & PAWELEC, G. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1396.043 · Cited by 242 · see citing works
Blyth, E., Clancy, L. E., Simms, R. M., Chun, K. K., Burgess, J. S., Deo, S. S., Byth, K., Dubosq, M., Shaw, P. J., Micklethwaite, K. P., et al. (2013) · Blood · doi:10.1182/blood-2012-08-448977 · Cited by 234 · see citing works
“52 ALL 7 (14) 8 (14) 24 (19) CML — — 5 (4) MDS 2 (4) 3 (6) 4 (3) NHL 5 (10) 6 (11) 15 (12) HD 1 (2) — 1 (1) MM 2 (4) 2 (4) 3 (2) Other 3 (6) 4 (7) 12 (9) Stage of disease CR1 18 (36) 19 (35) 50 (39) .”
BackgroundInfluentialKharfan‐Dabaja, M. A., Boeckh, M., Wilck, M. B., Langston, A. A., Chu, A. H., Wloch, M. K., Guterwill, D. F., Smith, L. R., Rolland, A. P., & Kenney, R. T. (2012) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(11)70344-9 · Cited by 231 · see citing works
John, S., Yuzhakov, O., Woods, A., Deterling, J., Hassett, K., Shaw, C. A., & Ciaramella, G. (2018) · Vaccine · doi:10.1016/j.vaccine.2018.01.029 · Cited by 229 · see citing works
“T cell responses in CMV seropositive individuals predominantly target epitopes within the pp65 and IE1 antigens [42-44].”
Pitard, V., Roumanes, D., Lafarge, X., Couzi, L., Garrigue, I., Lafon, M., Merville, P., Moreau, J., & Déchanet-Merville, J. (2008) · Blood · doi:10.1182/blood-2008-01-136713 · Cited by 250 · see citing works
“CMVseronegative (n 80) and CMV-seropositive (n 106) donor groups had comparable mean ages (mean [range] 40 [19-60] years vs 41 [19-59] years, respectively, P .”
BackgroundWhite, K. D., Chung, W., Chung, W., Mallal, S. A., & Phillips, E. J. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.05.050 · Cited by 224 · see citing works
“Multiple studies have demonstrated that CMVspecific CD4(1) and CD8(1) T cells account for a major proportion of the total memory T-cell repertoire in CMV-seropositive adults and that this proportion increases with aging (estimated to be 10% to 40% of the total CD4(1) repertoire and up to 10% of the total CD8(1) repert…”
BackgroundPeggs, K. S., Thomson, K. J., Samuel, E. R., Dyer, G., Armoogum, J., Chakraverty, R. K., Pang, K., Mackinnon, S., & Lowdell, M. W. (2010) · Clinical Infectious Diseases · doi:10.1093/cid/ciq042 · Cited by 225 · see citing works
Human Cytomegalovirus Latency: Approaching the Gordian Knot
Goodrum, F. D. (2016) · Annual Review of Virology · doi:10.1146/annurev-virology-110615-042422 · Cited by 224 · see citing works
“The expansion of CMV-specific T cells likely reflects the broad repertoire of responding T cells (23), low-level, repeated antigen exposure from frequent viral reactivation, and superinfection (27).”
BackgroundLiu, L. L., Landskron, J., Ask, E. H., Enqvist, M., Sohlberg, E., Traherne, J. A., Hammer, Q., Goodridge, J. P., Larsson, S., Jayaraman, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.005 · Cited by 222 · see citing works
“HCMV-specific T cells have a terminally differentiated phenotype and can represent up to 40% of the total T cell memory pool (Sylwester et al., 2005; van Lier et al., 2003).”
BackgroundBiomarkers of human immunosenescence: impact of cytomegalovirus infection
Derhovanessian, E., Larbi, A., & Pawelec, G. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.05.012 · Cited by 220 · see citing works
Bernstein, D. I., Reap, E. A., Katen, K., Watson, A., Smith, K., Norberg, P., Olmsted, R. A., Hoeper, A., Morris, J., Negri, S., et al. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.09.135 · Cited by 212 · see citing works
Role of CMV in immune senescence.
Pawelec, G., & Derhovanessian, E. (2011) · Virus Research · doi:10.1016/j.virusres.2010.09.010 · Cited by 201 · see citing works
Neidleman, J., Luo, X., Frouard, J., Xie, G., Gill, G., Stein, E. S., McGregor, M., Ma, T., George, A. F., Kosters, A., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100081 · Cited by 188 · see citing works
Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation
Hertoghs, K. M. L., Moerland, P. D., van Stijn, A., Remmerswaal, E. B. M., Yong, S. L., van de Berg, P. J. E. J., van Ham, S. M., Baas, F., ten Berge, I. J. M., & van Lier, R. A. W. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42758 · Cited by 198 · see citing works
Extensive Genome-Wide Variability of Human Cytomegalovirus in Congenitally Infected Infants
Renzette, N., Bhattacharjee, B., Jensen, J. D., Gibson, L. L., & Kowalik, T. F. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1001344 · Cited by 200 · see citing works
“[52] to further investigate the patterns of intrahost diversity (Figures 4 and S6).”
BackgroundSoroceanu, L., & Cobbs, C. (2010) · Virus Research · doi:10.1016/j.virusres.2010.10.026 · Cited by 195 · see citing works
“Indeed, recurrent viral reactivation appears to result in a chronic immune response to the virus often characterized by a specific anti-HCMV T lymphocyte response of over 10% of circulating lymphocytes in immunocompetent individuals (Sylwester et al., 2005).”
BackgroundImmunomic Analysis of the Repertoire of T-Cell Specificities for Influenza A Virus in Humans
Assarsson, E., Bui, H., Sidney, J., Zhang, Q., Glenn, J., Oseroff, C., Mbawuike, I. N., Alexander, J., Newman, M. J., Grey, H. M., et al. (2008) · Journal of Virology · doi:10.1128/jvi.01563-08 · Cited by 193 · see citing works
“This observation is in agreement with results for the vaccinia virus and cytomegalovirus systems, where a remarkably diverse pattern of immune recognition has been described in humans (18, 19, 29 ).”
BackgroundResultInfluentialHIV as a Cause of Immune Activation and Immunosenescence
Sokoya, T., Steel, H. C., Nieuwoudt, M., & Rossouw, T. M. (2017) · Mediators of Inflammation · doi:10.1155/2017/6825493 · Cited by 194 · see citing works
Naeger, D. M., Martin, J. N., Sinclair, E., Hunt, P. W., Bangsberg, D. R., Hecht, F. M., Hsue, P. Y., McCune, J. M., & Deeks, S. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008886 · Cited by 190 · see citing works
“We favor an indirect effect of CMV on outcome via the strong proinflammatory role that CMV appears to have in vivo [28].”
BackgroundMethodResultInfluentialImmunosenescence and Immunogenetics of Human Longevity
Ostan, R., Bucci, L., Capri, M., Salvioli, S., Scurti, M., Pini, E., Monti, D., & Franceschi, C. (2008) · NeuroImmunoModulation · doi:10.1159/000156466 · Cited by 188 · see citing works
“underlining the importance of CMV infection in human immunosenescence.Sylwester et al. [”
BackgroundMechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection
Tu, W., & Rao, S. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.02111 · Cited by 189 · see citing works
The Immune Response to Human CMV
Rosa, C. L., & Diamond, D. J. (2012) · Future Virology · doi:10.2217/fvl.12.8 · Cited by 190 · see citing works
The impact of differential antiviral immunity in children and adults
Prendergast, A. J., Klenerman, P., & Goulder, P. (2012) · Nature reviews. Immunology · doi:10.1038/nri3277 · Cited by 190 · see citing works
Aspects of Human Cytomegalovirus Latency and Reactivation
Reeves, M. B., & Sinclair, J. H. (2008) · Current topics in microbiology and immunology · doi:10.1007/978-3-540-77349-8_17 · Cited by 187 · see citing works
“This may be the reason for the unprecedented number of memory T cells that recognise lytic HCMV antigens from healthy carriers in vivo (Riddell et al. 1991; McLaughlin-Taylor et al. 1994; Wills et al. 1996; Sylwester et al. 2005 ).”
BackgroundLichtner, M., Cicconi, P., Vita, S., Cozzi‐Lepri, A., Galli, M., Caputo, S. L., Saracino, A., Luca, A. D., Moioli, M. C., Maggiolo, F., et al. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu417 · Cited by 187 · see citing works
“antigen-specific T cells [48, 49], it is also associated with a higher frequency of subclinical atherosclerosis in HIV-infected women and men [9, 13].”
BackgroundDerhovanessian, E., Maier, A. B., Hähnel, K., Beck, R., de Craen, A. J. M., Slagboom, P. E., Westendorp, R. G. J., & Pawelec, G. (2011) · Journal of General Virology · doi:10.1099/vir.0.036004-0 · Cited by 186 · see citing works
“In the case of human cytomegalovirus (CMV), a high proportion of both CD4 and CD8 T-cells in the peripheral blood of asymptomatic infected individuals respond specifically to different antigens derived from this single virus (Sylwester et al., 2005).”
BackgroundZaunders, J. J., Munier, C. M. L., Seddiki, N., Pett, S. L., Ip, S., Bailey, M., Xu, Y., Brown, K., Dyer, W. B., Kim, M., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803548 · Cited by 184 · see citing works
“It should be noted that in one study investigating the total response to CMV, 10% of memory CD4 T cells responded to all available antigenic peptides (29).”
BackgroundSimon, C. O., Holtappels, R., Tervo, H.-M., Böhm, V., Däubner, T., Oehrlein-Karpi, S. A., Kühnapfel, B., Renzaho, A., Strand, D., Podlech, J., et al. (2006) · Journal of Virology · doi:10.1128/jvi.01248-06 · Cited by 182 · see citing works
“Likewise, by testing the response of 33 latently infected, healthy volunteers covering a wide range of MHC (HLA) alleles, a genome-wide analysis of antigenic open reading frames (ORFs) of hCMV has shown great variance between individuals, ranging from 1 ORF to 32 ORFs recognized by CD8 T cells of an individual (89).”
BackgroundInfluentialCMV and Immunosenescence: from basics to clinics
Solana, R., Tarazona, R., Aiello, A. E., Akbar, A. N., Appay, V., Beswick, M., Bosch, J. A., Campos, C., Cantisán, S., Čičin‐Šain, L., et al. (2012) · Immunity & Ageing · doi:10.1186/1742-4933-9-23 · Cited by 181 · see citing works
“Kern (Brighton, UK) presented an analysis of T cell response to 19 different CMV targets previously identified to be the most relevant CD4 and CD8 T-cell target antigens in the CMV proteome [9].”
MethodSelf-citationPangrazzi, L., & Weinberger, B. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.110887 · Cited by 180 · see citing works
Hersperger, A. R., Martin, J. N., Shin, L. Y., Sheth, P. M., Kovacs, C. M., Cosma, G. L., Makedonas, G., Pereyra, F., Walker, B. D., Kaul, R., et al. (2011) · Blood · doi:10.1182/blood-2010-12-322727 · Cited by 180 · see citing works
Vescovini, R., Biasini, C., Fagnoni, F. F., Telera, A. R., Zanlari, L., Pedrazzoni, M., Bucci, L., Monti, D., Medici, M. C., Chezzi, C., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.4283 · Cited by 173 · see citing works
“Indeed, both Ags induced production of IFN- and TNFby a number of circulating T cells several times greater in old and very old subjects than in younger donors.”
BackgroundInfluentialEx vivo monitoring of human cytomegalovirus‐specific CD8+ T‐cell responses using QuantiFERON®‐CMV
Walker, S., Fazou, C., Crough, T., Holdsworth, R. F., Kiely, P., Veale, M. C., Bell, S. C., Gailbraith, A., McNeil, K., Jones, S., et al. (2007) · Transplant Infectious Disease · doi:10.1111/j.1399-3062.2006.00199.x · Cited by 173 · see citing works
“... function in suppressing HCMV replication is also highlighted by the fact that adoptive transfer or reconstitution of CD8 1 HCMV-specific cytotoxicT lymphocytes (CTLs) can protect against virus-associated pathogenesis (2, 6, 7 ). Recent studies have shown that the enumeration of CD81HCMV-specific T cells in immunos…”
BackgroundGain and loss of T cell subsets in old age: age-related reshaping of the T cell repertoire.
Arnold, C. R., Wolf, J., Brunner, S., Herndler-Brandstetter, D., & Grubeck-Loebenstein, B. (2011) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9499-x · Cited by 170 · see citing works
“Persistent infection with CMV and the consequent accumulation of pro-inflammatory CD8+CD28- T cells have also been associated with an enhanced risk of coronary heart disease and impaired vascular function [104–106].”
BackgroundInfluentialSuessmuth, 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
Does intra-individual major histocompatibility complex diversity keep a golden mean?
Woelfing, B., Traulsen, A., Milinski, M., & Boehm, T. L. J. (2008) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.0174 · Cited by 170 · see citing works
Appay, 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
Cevenini, E., Caruso, C., Candore, G., Capri, M., Nuzzo, D., Duro, G., Rizzo, C., Colonna‐Romano, G., Lio, D., Carlo, D., et al. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210790883840 · Cited by 166 · see citing works
“Healthy seropositive subjects aged 19-55 years are able to maintain CMV under control by broadly targeting the overall CMV proteome with about 10% of both CD4 + and CD8 + peripheral T cells which produce intracellular interferon (IFN)- [19]; however a much larger percentage (2050%) of T cells are involved in protectin…”
BackgroundThe role of oxidative and inflammatory stress and persistent viral infections in immunosenescence
Bauer, M. E., & la Fuente, M. D. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.01.001 · Cited by 164 · see citing works
Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo
Simonetti, F. R., Zhang, H., Soroosh, G., Duan, J., Rhodehouse, K., Hill, A. L., Beg, S. A., McCormick, K., Raymond, H. E., Nobles, C. L., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci145254 · Cited by 160 · see citing works
Hallmark Features of Immunosenescence Are Absent in Familial Longevity
Derhovanessian, E., Maier, A. B., Beck, R., Jahn, G., Hähnel, K., Slagboom, P. E., de Craen, A. J. M., Westendorp, R. G. J., & Pawelec, G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001629 · Cited by 164 · see citing works
“is committed to controlling the virus (even up to as much as 30% of CD4 and CD8 memory responses in some individuals) (5).”
BackgroundImmunosenenescence: role of cytomegalovirus
Pawelec, G. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2013.11.010 · Cited by 163 · see citing works
“010 peripheral CD4+ and CD8+ T cell repertoire to recognizing many different antigens from CMV (Sylwester et al., 2005).”
InfluentialDetection of Intracellular Cytokines by Flow Cytometry
Yin, Y., Mitson‐Salazar, A., & Prussin, C. (2015) · Current Protocols in Immunology · doi:10.1002/0471142735.im0624s110 · Cited by 162 · see citing works
“…activation are contained in this unit; however, these protocols will work with any number of stimuli including anti-CD3, lectin, antigens (Waldrop et al., 1997; Kagina et al., 2015), peptide antigens (Maecker et al., 2001; Sylwester et al., 2005; McDermott et al., 2014), allergens…”
BackgroundCytomegalovirus in Hematopoietic Stem Cell Transplant Recipients
Ljungman, P. T., Hakki, M., & Boeckh, M. (2010) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2010.01.008 · Cited by 161 · see citing works
Immunodominant Tuberculosis CD8 Antigens Preferentially Restricted by HLA-B
Lewinsohn, D. A., Winata, E., Swarbrick, G. M., Tanner, K. E., Cook, M. S., Null, M. D., Cansler, M. E., Sette, A., Sidney, J., & Lewinsohn, D. M. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030127 · Cited by 154 · see citing works
“]. Finally, given the very high-frequency responses that we and others have observed to Mtb-infected DCs and to single antigens, it appears that the immune response to Mtb occupies a sizable fraction of the host's immunological activity, similar to that previously observed for infection with CMV [”
ResultKumar, D., Mian, M. F., Singer, L. G., & Humar, A. (2017) · American Journal of Transplantation · doi:10.1111/ajt.14347 · Cited by 159 · see citing works
“Duration of prophylaxis (months); median (range) 3 (1-12) 3 (2-9) 0.”
BackgroundCytomegalovirus Infection Reduces Telomere Length of the Circulating T Cell Pool
van de Berg, P. J. E. J., Griffiths, S. J., Yong, S.-L., Macaulay, R., Bemelman, F. J., Jackson, S., Henson, S. M., ten Berge, I. J. M., Akbar, A. N., & van Lier, R. A. W. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903442 · Cited by 157 · see citing works
“reading frames of CMV have shown that both CD4 and CD8 responses occupy an unprecedented part of the T cell response (32).”
BackgroundImmune modulation during latent herpesvirus infection
White, D. W., Beard, R. S., & Barton, E. S. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01074.x · Cited by 155 · see citing works
“Approximately 10–20% of circulating memory CD4 and CD8 T cells in healthy adults is specific for HCMV antigens (16).”
BackgroundNew advances in CMV and immunosenescence
Sansoni, P., Vescovini, R., Fagnoni, F. F., Akbar, A., Arens, R., Chiu, Y.-L., Čičin-Šain, L., Dechanet-Merville, J., Derhovanessian, E., Ferrando-Martinez, S., et al. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.03.020 · Cited by 150 · see citing works
“In a recent study, F.Kern (Brighton, UK), reported on a large T cell response dataset from short-term ex-vivo HCMV antigen stimulation (measured by IFN-γ secretion) (Sylwester et al., 2005).”
BackgroundSelf-citationDay, E., Carmichael, A., ten Berge, I. J. M., Waller, E. C. P., Sissons, J. G. P., & Wills, M. R. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.5.3203 · Cited by 153 · 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
Egli, A., Humar, A., & Kumar, D. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cis818 · Cited by 152 · see citing works
“In one study, 151 CMV open reading frames (ORFs) were immunogenic for CD4 and/or CD8 T cells, sharing 8 of 15 top recognized ORFs [22].”
Cytomegalovirus: Shape-Shifting the Immune System
Picarda, G. G. A., & Benedict, C. A. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800171 · Cited by 152 · see citing works
“As in mice, CMV induces a broad CD8 and CD4 T cell response that typically comprises 10–20% of all circulating T cells in CMV persons (79).”
BackgroundZhou, W., Longmate, J., Lacey, S. F., Palmer, J. M., Gallez-Hawkins, G. M., Thao, L., Spielberger, R. T., Nakamura, R., Forman, S. J., Zaia, J. A., et al. (2009) · Blood · doi:10.1182/blood-2009-02-203307 · Cited by 151 · see citing works
Bakker, A., Hoppes, R., Linnemann, C., Toebes, M., Rodenko, B., Berkers, C. R., Hadrup, S. R., van Esch, W. J. E., Heemskerk, M. H. M., Ovaa, H., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709717105 · Cited by 151 · see citing works
Novel viral vectors in infectious diseases
Humphreys, I. R., & Sebastian, S. (2017) · Immunology · doi:10.1111/imm.12829 · Cited by 148 · see citing works
- 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
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.
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