Cytotoxic CD4+ T cell responses to EBV contrast with CD8 responses in breadth of lytic cycle antigen choice and in lytic cycle recognition
Open accessAbstract
EBV, a B lymphotropic herpesvirus, encodes two immediate early (IE)-, >30 early (E)-, and >30 late (L)-phase proteins during its replication (lytic) cycle. Despite this, lytic Ag-induced CD8 responses are strongly skewed toward IE and a few E proteins only, all expressed before HLA I presentation is blocked in lytically infected cells. For comparison, we examined CD4+ T cell responses to eight IE, E, or L proteins, screening 14 virus-immune donors to overlapping peptide pools in IFN-γ ELISPOT assays, and established CD4+ T cell clones against 12 defined epitopes for target-recognition assays. We found that the lytic Ag-specific CD4+ T cell response differs radically from its CD8 counterpart in that it is widely distributed across IE, E, and L Ag targets, often with multiple reactivities detectable per donor and with IE, E, or L epitope responses being numerically dominant, and that all CD4+ T cell clones, whether IE, E, or L epitope-specific, show strong recognition of EBV-transformed B cell lines, despite the lines containing only a small fraction of lytically infected cells. Efficient recognition occurs because lytic Ags are released into the culture and are acquired and processed by neighboring latently infected cells. These findings suggested that lytic Ag-specific CD4 responses are driven by a different route of Ag display than drives CD8 responses and that such CD4 effectors could be therapeutically useful against EBV-driven lymphoproliferative disease lesions, which contain similarly small fractions of EBV-transformed cells entering the lytic cycle.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Senescent T cells within both CD4+ and CD8+ subsets express high levels of intracellular granules containing perforin and granzyme B and can mediate spontaneous antigen-specific cytotoxicity against infected target cells.
“Senescent T cells within both CD4 + and CD8 + subsets express high levels of intracellular granules containing the cytotoxic proteins perforin and granzyme B and can mediate spontaneous antigen-specific cytotoxicity against infected target cells [47-49].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [49]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Rickinson, A. B. (2002) · PubMed · doi:10.1016/s0168-1702(01)00436-1 · Cited by 2,182 · see citing works
Self-citationSelectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine
Elion, G. B., Furman, P. A., Fyfe, J. A., de Miranda, P., Beauchamp, L. M., & Schaeffer, H. J. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.12.5716 · Cited by 1,591 · see citing works
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., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050882 · Cited by 1,339 · cited 1× · see citing works
“Such concordance between CD8 immunodominance among lytic-cycle Ags and their kinetics of expression in lytically infected cells is a specific feature of the EBV system is and not seen, for example, in another herpesvirus encoding multiple inhibitors of the HLA I pathway, human CMV (18).”
BackgroundEndogenous MHC Class II Processing of a Viral Nuclear Antigen After Autophagy
Paludan, C., Schmid, D., Landthaler, M., Vockerodt, M., Kube, D., Tuschl, T., & Münz, C. (2005) · Science · doi:10.1126/science.1104904 · Cited by 860 · cited 3× · see citing works
“There are trends in target Ag choice, such that several (but not all) epitopes eliciting the strongest CD8 responses derive from the EBNA3 Ags, whereas up to half of the currently defined CD4 epitopes (but not necessarily those eliciting the strongest responses) derive from EBNA1 (1).”
BackgroundCellular responses to viral infection in humans: lessons from Epstein–Barr virus
Hislop, A. D., Taylor, G. S., Sauce, D., & Rickinson, A. B. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141553 · Cited by 766 · see citing works
Self-citationHaque, T., Wilkie, G. M., Jones, M. M., Higgins, C. D., Urquhart, G., Wingate, P. J., Burns, D., McAulay, K. A., Turner, M., Bellamy, C. O. C., et al. (2007) · Blood · doi:10.1182/blood-2006-12-063008 · Cited by 646 · see citing works
A Re-Evaluation of the Frequency of CD8+ T Cells Specific for EBV in Healthy Virus Carriers
Tan, L., Gudgeon, N. H., Annels, N. E., Hansasuta, P., O’Callaghan, C. A., Rowland‐Jones, S., McMichael, A. J., Rickinson, A. B., & Callan, M. F. C. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.3.1827 · Cited by 499 · see citing works
Self-citationPost-Transplant Lymphoproliferative Disorders
Gottschalk, S. M., Rooney, C. M., & Heslop, H. E. (2004) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104727 · Cited by 490 · see citing works
Feederle, R., Kost, M., Baumann, M., Janz, A., Drouet, E., Hammerschmidt, W., & Delecluse, H. (2000) · The EMBO Journal · doi:10.1093/emboj/19.12.3080 · Cited by 387 · see citing works
Leen, A. M., Meij, P., Redchenko, I., Middeldorp, J. M., Bloemena, E., Rickinson, A. B., & BLAKE, N. W. (2001) · Journal of Virology · doi:10.1128/jvi.75.18.8649-8659.2001 · Cited by 230 · see citing works
Self-citationAmyes, E., Hatton, C., Montamat‐Sicotte, D., Gudgeon, N. H., Rickinson, A. B., McMichael, A. J., & Callan, M. F. C. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20022058 · Cited by 225 · see citing works
Self-citationDetection of T-Cell Degranulation: CD107a and b
Betts, M. R., & Koup, R. A. (2004) · Methods in cell biology · doi:10.1016/s0091-679x(04)75020-7 · Cited by 215 · see citing works
Zuo, J., Currin, A., Griffin, B. D., Shannon-Lowe, C. D., Thomas, W. A., Ressing, M. E., Wiertz, E. J. H. J., & Rowe, M. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000255 · Cited by 206 · see citing works
Self-citationLatent and Replicating Forms of Epstein-Barr Virus DNA in Lymphomas and Lymphoproliferative Diseases
Katz, B. Z., Raab‐Traub, N., & Miller, G. (1989) · The Journal of Infectious Diseases · doi:10.1093/infdis/160.4.589 · Cited by 198 · see citing works
Epstein-Barr Nuclear Antigen 1-Specific CD4+ Th1 Cells Kill Burkitt’s Lymphoma Cells
Paludan, C., Bickham, K. L., Nikiforow, S., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.3.1593 · Cited by 173 · see citing works
Pudney, V. A., Leese, A. M., Rickinson, A. B., & Hislop, A. D. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041542 · Cited by 154 · see citing works
Self-citationControl of Epstein-Barr virus infection in vitro by T helper cells specific for virion glycoproteins
Adhikary, D., Behrends, U., Moosmann, A., Witter, K., Bornkamm, G. W., & Mautner, J. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051287 · Cited by 145 · see citing works
Comparison of overlapping peptide sets for detection of antiviral CD8 and CD4 T cell responses
Draenert, R., Altfeld, M. A., Brander, C., Basgoz, N. O., Corcoran, C. P., Wurcel, A. G., Stone, D. R., Kalams, S. A., Piechocka‐Trocha, A., Addo, M. M., et al. (2003) · Journal of Immunological Methods · doi:10.1016/s0022-1759(02)00541-0 · Cited by 134 · see citing works
Long, H. M., Haigh, T. A., Gudgeon, N. H., Leen, A. M., Tsang, C.-W., Brooks, J. M., Landais, E., Houssaint, E., Lee, S. P., Rickinson, A. B., et al. (2005) · Journal of Virology · doi:10.1128/jvi.79.8.4896-4907.2005 · Cited by 129 · see citing works
Self-citationShannon-Lowe, C. D., Adland, E., Bell, A. I., Delecluse, H., Rickinson, A. B., & Rowe, M. (2009) · Journal of Virology · doi:10.1128/jvi.00108-09 · Cited by 129 · see citing works
Self-citationLeung, C., Haigh, T., Mackay, L. K., Rickinson, A., & Taylor, G. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0909448107 · Cited by 123 · see citing works
Self-citationZuo, J., Thomas, W., van Leeuwen, D., et al. (2007) · Journal of Virology · doi:10.1128/jvi.01946-07 · Cited by 101 · see citing works
Réa, D., Fourcade, C., Leblond, V., et al. (1994) · Transplantation · doi:10.1097/00007890-199408000-00012 · Cited by 98 · see citing works
Croft, N. P., Shannon‐Lowe, C., Bell, A. I., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000490 · Cited by 96 · see citing works
Self-citationAdhikary, D., Behrends, U., Boerschmann, H., Pfünder, A., Burdach, S. E. G., Moosmann, A., Witter, K., Bornkamm, G. W., & Mautner, J. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000583 · Cited by 91 · see citing works
Omiya, R., Buteau, C., Kobayashi, H., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.4.2172 · Cited by 87 · see citing works
Khanna, R., Burrows, S. R., Steigerwald-Mullen, P. M., et al. (1995) · Virology · doi:10.1006/viro.1995.0076 · Cited by 84 · see citing works
Li, D., Qian, L., Chen, C.-G., Shi, M., Yu, M., Hu, M.-R., Song, L., Shen, B., & Guo, N. (2009) · Journal of Immunology · doi:10.4049/jimmunol.0802686 · Cited by 83 · see citing works
Keating, S. E., Prince, S., Jones, M., et al. (2002) · Journal of Virology · doi:10.1128/jvi.76.16.8179-8188.2002 · Cited by 82 · see citing works
Landais, E., Saulquin, X., Scotet, E., Trautmann, L., Peyrat, M., Yates, J. L., Kwok, W. W., Bonneville, M., & Houssaint, E. (2003) · Blood · doi:10.1182/blood-2003-03-0930 · Cited by 75 · see citing works
The wide diversity and complexity of peptides bound to class II MHC molecules.
Suri, A., Lovitch, S., & Unanue, E. (2006) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.11.002 · Cited by 75 · see citing works
Kt, M., Hodinka, R. L., Ke, S., et al. (1996) · PubMed · Cited by 72 · see citing works
Haigh, T. A., Lin, X., Jia, H., Hui, E. P., Chan, A. T. �., Rickinson, A. B., & Taylor, G. S. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.3.1643 · Cited by 71 · see citing works
Self-citationTaylor, G. S., Long, H. M., Haigh, T. A., Larsen, M., Brooks, J., & Rickinson, A. B. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3746 · Cited by 69 · see citing works
Self-citationShannon-Lowe, C. D., Baldwin, G., Feederle, R., Bell, A. I., Rickinson, A. B., & Delecluse, H. (2005) · Journal of General Virology · doi:10.1099/vir.0.81153-0 · Cited by 64 · see citing works
Self-citationThe immune response to Epstein–Barr virus
Callan, M. F. C. (2004) · Microbes and Infection · doi:10.1016/j.micinf.2004.04.014 · Cited by 63 · see citing works
Rowe, M., & Zuo, J. (2009) · Microbes and Infection · doi:10.1016/j.micinf.2009.12.001 · Cited by 57 · see citing works
Scherrenburg, J., Piriou, E., Nanlohy, N. M., & van Baarle, D. (2008) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2008.03699.x · Cited by 57 · see citing works
Epstein‐Barr virus nuclear antigen 1 evades direct immune recognition by CD4+ T helper cells
Mautner, J., Pich, D., Nimmerjahn, F., Milosevic, S., Adhikary, D., Christoph, H., Witter, K., Bornkamm, G. W., Hammerschmidt, W., & Behrends, U. (2004) · European Journal of Immunology · doi:10.1002/eji.200324794 · Cited by 56 · see citing works
Wallace, L. E., Wright, J., Ulaeto, D., et al. (1991) · Journal of Virology · doi:10.1128/jvi.65.7.3821-3828.1991 · Cited by 53 · see citing works
Virus-Specific Cytotoxic CD4+ T Cells for the Treatment of EBV-Related Tumors
Merlo, A., Turrini, R., Bobisse, S., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902850 · Cited by 49 · see citing works
Mackay, L. K., Long, H. M., Brooks, J., Taylor, G., Leung, C., Chen, A., Wang, F., & Rickinson, A. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000699 · Cited by 43 · see citing works
Self-citationThe role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection
Mautner, J., & Bornkamm, G. W. (2011) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2011.01.007 · Cited by 42 · see citing works
Gudgeon, N. H., Taylor, G. S., Long, H. M., et al. (2005) · Journal of Virology · doi:10.1128/jvi.79.9.5477-5488.2005 · Cited by 40 · see citing works
Self-citationFeederle, R., Shannon‐Lowe, C., Baldwin, G., et al. (2005) · Journal of Virology · doi:10.1128/jvi.79.12.7641-7647.2005 · Cited by 39 · see citing works
Self-citationAdhikary, D., Behrends, U., Feederle, R., Delecluse, H., & Mautner, J. (2008) · Journal of Virology · doi:10.1128/jvi.02227-07 · Cited by 39 · see citing works
Brooks, J. M., Lee, S. P., Leese, A. M., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0713607 · Cited by 34 · see citing works
Self-citationBhaduri‐McIntosh, S., Rotenberg, M. J., Gardner, B., et al. (2007) · Blood · doi:10.1182/blood-2007-07-101907 · Cited by 30 · see citing works
Landais, E., Saulquin, X., Bonneville, M., & Houssaint, E. (2005) · Journal of Immunology · doi:10.4049/jimmunol.175.12.7939 · Cited by 25 · see citing works
Sauce, D., Larsen, M., Abbott, R. J. M., Hislop, A. D., Leese, A. M., Khan, N., Papagno, L., Freeman, G. J., & Rickinson, A. B. (2009) · Journal of Virology · doi:10.1128/jvi.00141-09 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
Akbar, A. N., Henson, S. M., & Lanna, A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.09.002 · Cited by 285 · see citing works
Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?
Juno, J. A., van Bockel, D., Kent, S. J., Kelleher, A. D., Zaunders, J. J., & Munier, C. M. L. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00019 · Cited by 195 · see citing works
- Authors
- Long, H. M., Leese, A. M., Chagoury, O. L., Connerty, S. R., Quarcoopome, J., Quinn, L. L., Shannon-Lowe, C., & Rickinson, A. B.
- Affiliations
- University of Birmingham (GB)
- Corresponding author
- Rickinson, Alan B
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-07-01
- Volume
- 187
- Issue
- 1
- Pages
- 92-101
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3154640
- OpenAlex
- W2161252431
- Cited by
- 79
- References
- 50
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 2 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 7 · 2013: 5 · 2012: 3
- FWCI
- 2.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Leukaemia and Lymphoma Research
- U.S. Public Health Service (G0901755-E02/1)
- Medical Research Council (G0901755)
- Topics
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Keywords
- Epstein-Barr virus, CD4+ T cell responses, CD8+ T cell responses, immediate-early proteins, early proteins, late proteins, antigen presentation, HLA class I, EBV-transformed B cell lines, T cell clones
- MeSH terms
- Antigens, Viral, Cells, Cultured, Clone Cells, Cytotoxicity Tests, Immunologic, Herpesvirus 4, Human, Humans, Interferon-gamma, Phosphoproteins, Virus Replication, CD4-Positive T-Lymphocytes, Trans-Activators, Gene Expression Regulation, Viral, Immediate-Early Proteins, CD8-Positive T-Lymphocytes, Epitope Mapping, Epitopes, T-Lymphocyte
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
