T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions
Abstract
Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Without licensing signal, activated helpless CTLs function as primary effector T cells but have a short lifespan or die via activation-induced cell death after subsequent antigen exposure.
“Without this additional signal, the activated ‘helpless’ CTL function as primary effector T cells but with a short lifespan69 or die via activation-induced cell death following subsequent exposure to antigen70,71.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [69]
Cites
The Dendritic Cell System and its Role in Immunogenicity
Steinman, R. M. (1991) · Annual Review of Immunology · doi:10.1146/annurev.iy.09.040191.001415 · Cited by 4,659 · see citing works
Cella, M., Scheidegger, D., Palmer-Lehmann, K., Lane, P. J. L., Lanzavecchia, A., & Alber, G. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.2.747 · Cited by 1,982 · see citing works
Kitamura, D., Roes, J., Kühn, R., & Rajewsky, K. (1991) · Nature · doi:10.1038/350423a0 · Cited by 1,783 · see citing works
Dialynas, D. P., Quan, Z., Wall, K. A., Pierrès, A., Quintáns, J., Loken, M. R., Pierres, M., & Fitch, F. W. (1983) · The Journal of Immunology · doi:10.4049/jimmunol.131.5.2445 · Cited by 1,273 · see citing works
Role of Bone Marrow-Derived Cells in Presenting MHC Class I-Restricted Tumor Antigens
Huang, A. Y.-C., Golumbek, P. T., Ahmadzadeh, M., Jaffee, E. M., Pardoll, D. M., & Levitsky, H. I. (1994) · Science · doi:10.1126/science.7513904 · Cited by 1,159 · see citing works
Mayordomo, J. I., Zorina, T. D., Storkus, W. J., Zitvogel, L., Celluzzi, C. M., Falo, L. D., Melief, C. J. M., Ildstad, S. T., Kast, W. M., DeLeo, A. B., et al. (1995) · Nature Medicine · doi:10.1038/nm1295-1297 · Cited by 1,075 · see citing works
Self-citationBevan, M. J. (1976) · The Journal of Experimental Medicine · doi:10.1084/jem.143.5.1283 · Cited by 962 · see citing works
Koch, F., Stanzl, U., Jennewein, P., Janke, K., Heufler, C., Kämpgen, E., Romani, N., & Schuler, G. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.2.741 · Cited by 928 · see citing works
Noelle, R. J., Roy, M., Shepherd, D. M., Stamenkovic, I., Ledbetter, J. A., & Aruffo, A. A. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.14.6550 · Cited by 805 · see citing works
Bennett, S. R. M., Carbone, F., Karamalis, F., Miller, J. F. A. P., & Heath, W. R. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.1.65 · Cited by 725 · see citing works
Kurts, C., Kosaka, H., Carbone, F., Miller, J. F. A. P., & Heath, W. R. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.2.239 · Cited by 706 · see citing works
Depletion of CD4 + T Cells in Major Histocompatibility Complex Class II-Deficient Mice
Grusby, M. J., Johnson, R. S., Papaioannou, V. E., & Glimcher, L. H. (1991) · Science · doi:10.1126/science.1910207 · Cited by 660 · see citing works
Helper activity is required for the in vivo generation of cytotoxic T lymphocytes
Keene, J.-A., & Forman, J. (1982) · The Journal of Experimental Medicine · doi:10.1084/jem.155.3.768 · Cited by 505 · see citing works
Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand
Grewal, I. S., Xu, J., & Flavell, R. A. (1995) · Nature · doi:10.1038/378617a0 · Cited by 472 · see citing works
CD40 Ligand-Dependent T Cell Activation: Requirement of B7-CD28 Signaling Through CD40
Yang, Y., & Wilson, J. M. (1996) · Science · doi:10.1126/science.273.5283.1862 · Cited by 433 · see citing works
CD40 ligand-transduced co-stimulation of T cells in the development of helper function
van Essen, D., Kikutani, H., & Gray, D. (1995) · Nature · doi:10.1038/378620a0 · Cited by 414 · see citing works
The SCID but Not the RAG-2 Gene Product Is Required for Sμ–Sε Heavy Chain Class Switching
Rolink, A. G., Melchers, F., & Andersson, J. (1996) · Immunity · doi:10.1016/s1074-7613(00)80258-7 · Cited by 404 · see citing works
A central role of CD40 ligand in the regulation of CD4+ T-cell responses
Grewal, I. S., & Flavell, R. A. (1996) · Immunology Today · doi:10.1016/0167-5699(96)10030-x · Cited by 327 · see citing works
Soong, L., Xu, J., Grewal, I. S., et al. (1996) · Immunity · doi:10.1016/s1074-7613(00)80434-3 · Cited by 306 · see citing works
Eradication of adenovirus E1-induced tumors by E1A-specific cytotoxic T lymphocytes
Kast, W. M., Offringa, R., Peters, P. J., Voordouw, A. C., Meloen, R. H., van der Eb, A. J., & Melief, C. J. M. (1989) · Cell · doi:10.1016/0092-8674(89)90006-8 · Cited by 301 · see citing works
Self-citationImpaired T cell-mediated macrophage activation in CD40 ligand-deficient mice
Stout, R. D., Suttles, J., Xu, J., Grewal, I. S., & Flavell, R. A. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.1.8 · Cited by 234 · see citing works
CD40 and Its Ligand in Host Defense
Noelle, R. J. (1996) · Immunity · doi:10.1016/s1074-7613(00)80408-2 · Cited by 232 · see citing works
Responsiveness to HY Antigen Ir Gene Complementation and Target Cell Specificity
Simpson, E., & Gordon, R. D. (1977) · Immunological Reviews · doi:10.1111/j.1600-065x.1977.tb00235.x · Cited by 215 · see citing works
A fail-safe mechanism for maintaining self-tolerance.
Guerder, S., & Matzinger, P. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.176.2.553 · Cited by 205 · see citing works
Induction of B cell costimulatory function by recombinant murine CD40 ligand
Kennedy, M. K., Mohler, K. M., Shanebeck, K. D., Baum, P. R., Picha, K. S., Otten-Evans, C., Janeway, C. A., & Grabstein, K. H. (1994) · European Journal of Immunology · doi:10.1002/eji.1830240118 · Cited by 142 · see citing works
Mackey, M., Gunn, J. R., Ting, P. P., Kikutani, H., Dranoff, G., Noelle, R. J., & Barth, R. J. (1997) · PubMed · Cited by 107 · see citing works
Shinde, S. S., Wu, Y. P., Guo, Y., Niu, Q., Xu, J., Grewal, I. S., Flavell, R. A., & Liu, Y. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.7.2764 · Cited by 97 · see citing works
Protective antitumor immunity induced by immunization with completely allogeneic tumor cells.
Toes, R. E. M., Blom, R. J. J., van der Voort, E., Offringa, R., Melief, C. J. M., & Kast, W. M. (1996) · PubMed · Cited by 86 · see citing works
Self-citationCooperation between Helper T Cells and Cytotoxic T Lymphocyte Precursors
HUSMANN, L. A., & Bevan, M. J. (1988) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1988.tb36335.x · Cited by 83 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
Sallusto, F., Geginat, J., & Lanzavecchia, A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104702 · Cited by 3,067 · see citing works
Tertiary lymphoid structures in the era of cancer immunotherapy
Sautès-Fridman, C., Petitprez, F., Calderaro, J., & Fridman, W. H. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0144-6 · Cited by 1,884 · see citing works
Effector and memory T-cell differentiation: implications for vaccine development
Kaech, S. M., Wherry, E. J., & Ahmed, R. (2002) · Nature Reviews Immunology · doi:10.1038/nri778 · Cited by 1,865 · see citing works
CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes
Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G., & Schoenberger, S. P. (2003) · Nature · doi:10.1038/nature01441 · Cited by 1,635 · see citing works
Self-citationSaxena, M., van der Burg, S. H., Melief, C. J. M., & Bhardwaj, N. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00346-0 · Cited by 1,581 · see citing works
Self-citationCD4+ T cell help in cancer immunology and immunotherapy
Borst, J., Ahrends, T., Bąbała, N., Melief, C. J. M., & Kastenmüller, W. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0044-0 · Cited by 1,585 · see citing works
Self-citationLei, X., Lei, Y., Li, J.-K., Du, W.-X., Li, R.-G., Yang, J., Li, J., Li, F., & Tan, H.-B. (2020) · Cancer Letters · doi:10.1016/j.canlet.2019.11.009 · Cited by 1,470 · see citing works
The Central Role of CD4+ T Cells in the Antitumor Immune Response
Hung, K., Hayashi, R., Lafond-Walker, A., Lowenstein, C., Pardoll, D., & Levitsky, H. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.12.2357 · Cited by 1,345 · see citing works
Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity
Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., Krzysiek, R., Knutson, K. L., Daniel, B., Zimmermann, M. C., et al. (2003) · Nature Medicine · doi:10.1038/nm863 · Cited by 1,314 · see citing works
Mutant MHC class II epitopes drive therapeutic immune responses to cancer
Kreiter, S., Vormehr, M., van de Roemer, N., Diken, M., Löwer, M., Diekmann, J., Boegel, S., Schrörs, B., Vascotto, F., Castle, J. C., et al. (2015) · Nature · doi:10.1038/nature14426 · Cited by 1,243 · see citing works
Self-citationDefective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help
Sun, J. C., & Bevan, M. J. (2003) · Science · doi:10.1126/science.1083317 · Cited by 1,213 · see citing works
Immunogenic and tolerogenic cell death
Green, D. R., Ferguson, T., Zitvogel, L., & Kroemer, G. (2009) · Nature Reviews Immunology · doi:10.1038/nri2545 · Cited by 1,176 · see citing works
van Elsas, A., Hurwitz, A. A., & Allison, J. P. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.3.355 · Cited by 1,020 · see citing works
Cross-Presentation, Dendritic Cells, Tolerance and Immunity
Heath, W. R., & Carbone, F. R. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.47 · Cited by 882 · see citing works
The multifaceted role of CD4+ T cells in CD8+ T cell memory
Laidlaw, B. J., Craft, J. E., & Kaech, S. M. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.10 · Cited by 657 · see citing works
TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy
Molgora, M., Esaulova, E., Vermi, W., Hou, J., Chen, Y., Luo, J., Brioschi, S., Bugatti, M., Omodei, A. S., Ricci, B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.013 · Cited by 656 · see citing works
“, 2015), as well as metabolic modulation, pharmacological modulation, and immunostimulation via an anti-CD40 agonistic antibody (Mantovani et al., 2017; Schoenberger et al., 1998; Wiehagen et al., 2017).”
cDC1 prime and are licensed by CD4(+) T cells to induce anti-tumour immunity
Ferris, S. T., Durai, V., Wu, R., Theisen, D. J., Ward, J. P., Bern, M. D., Davidson, J. T., Bagadia, P., Liu, T., Briseño, C. G., et al. (2020) · Nature · doi:10.1038/s41586-020-2611-3 · Cited by 611 · see citing works
CD40 agonist antibodies in cancer immunotherapy
Vonderheide, R. H. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-062518-045435 · Cited by 544 · see citing works
Cytokines in Cancer Immunotherapy
Waldmann, T. A. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028472 · Cited by 507 · see citing works
Robust Anti-Viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions
Eickhoff, S., Brewitz, A., Gerner, M. Y., Klauschen, F., Komander, K., Hemmi, H., Garbi, N., Kaisho, T., Germain, R. N., & Kastenmüller, W. (2015) · Cell · doi:10.1016/j.cell.2015.08.004 · Cited by 337 · see citing works
Tumor-infiltrating T lymphocytes: Friends or foes?
Yu, P., & Fu, Y.-X. (2006) · Laboratory Investigation · doi:10.1038/labinvest.3700389 · Cited by 299 · see citing works
Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses <i>in vitro</i>
Blank, C., Kuball, J., Voelkl, S., Wiendl, H., Becker, B., Walter, B., Majdic, O., Gajewski, T. F., Theobald, M., Andreesen, R., et al. (2006) · International Journal of Cancer · doi:10.1002/ijc.21775 · Cited by 297 · see citing works
CD40 stimulation obviates innate sensors and drives T cell immunity in cancer
Byrne, K. T., & Vonderheide, R. H. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.058 · Cited by 282 · see citing works
Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system
Lhuillier, C., Rudqvist, N.-P., Elemento, O., Formenti, S. C., & Demaria, S. (2019) · Genome Medicine · doi:10.1186/s13073-019-0653-7 · Cited by 276 · see citing works
Bachmann, M. F., Wong, B. R., Josien, R., Steinman, R. M., Oxenius, A., & Choi, Y. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.7.1025 · Cited by 260 · see citing works
T cell Allorecognition Pathways in Solid Organ Transplantation
Siu, J. H. Y., Surendrakumar, V., Richards, J. A., & Pettigrew, G. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02548 · Cited by 223 · see citing works
Why Aging T Cells Fail: Implications for Vaccination
Haynes, L., & Swain, S. L. (2006) · Immunity · doi:10.1016/j.immuni.2006.06.003 · Cited by 169 · see citing works
Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo
Haynes, L., Eaton, S. M., Burns, E. M., Rincon, M., & Swain, S. L. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.9.5194 · Cited by 162 · see citing works
Lleo, A., Liao, J., Invernizzi, P., Zhao, M., Bernuzzi, F., Ma, L., Lanzi, G., Ansari, A. A., Coppel, R. L., Zhang, P., et al. (2012) · Hepatology · doi:10.1002/hep.24630 · Cited by 133 · see citing works
CD40L expression permits CD8+ T cells to execute immunologic helper functions
Frentsch, M., Stark, R., Matzmohr, N., Meier, S., Durlanik, S., Schulz, A. R., Stervbo, U., Jürchott, K., Gebhardt, F., Heine, G., et al. (2013) · Blood · doi:10.1182/blood-2013-02-483586 · Cited by 100 · see citing works
Xia, M., Ling, W., Zhu, H., Wang, Q., Ma, J., Hou, M., Tang, Z., Li, L., & Ye, Q. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000254672.04573.2d · Cited by 96 · see citing works
Shirley, J. L., Keeler, G. D., Sherman, A., Zolotukhin, I., Markusic, D. M., Hoffman, B. E., Morel, L. M., Wallet, M. A., Terhorst, C., & Herzog, R. W. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.11.011 · Cited by 79 · see citing works
Widenmeyer, M., Griesemann, H., Stevanović, S., Feyerabend, S., Klein, R., Attig, S., Hennenlotter, J., Wernet, D., Kuprash, D. V., Sazykin, A. Y., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.26365 · Cited by 70 · see citing works
Regulation of the neurodegenerative process associated to Parkinson's disease by CD4+ T-cells
González, H., Contreras, F., & Pacheco, R. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9618-9 · Cited by 70 · see citing works
Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells
Mortenson, E. D., Park, S., Jiang, Z., Wang, S., & Fu, Y.-X. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2522 · Cited by 66 · see citing works
Epstein-Barr Virus and Multiple Sclerosis
Lünemann, J. D., & Münz, C. (2007) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-007-0038-y · Cited by 36 · see citing works
Age-associated parallel increase of Foxp3+CD4+ regulatory and CD44+CD4+ memory T cells in SJL/J mice
Han, G.-M., Zhao, B., Jeyaseelan, S., & Feng, J.-M. (2009) · Cellular Immunology · doi:10.1016/j.cellimm.2009.05.003 · Cited by 35 · see citing works
- Authors
- Schoenberger, S. P., Toes, R. E. M., van der Voort, E. I. H., Offringa, R., & Melief, C. J. M.
- Affiliations
- Leiden University Medical Center (NL)
- Leiden University (NL)
- Corresponding author
- Schoenberger, Stephen P.
- Venue
- Nature
- Published
- 1998-06
- Volume
- 393
- Issue
- 6684
- Pages
- 480-483
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1678167583
- Cited by
- 2,615
- References
- 29
- Citations by year
- 2026: 33 · 2025: 48 · 2024: 37 · 2023: 47 · 2022: 55 · 2021: 68 · 2020: 70 · 2019: 48 · 2018: 62 · 2017: 55 · 2016: 70 · 2015: 69 · 2014: 79 · 2013: 88 · 2012: 68
- FWCI
- 60.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- KWF Kankerbestrijding
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- CD40-CD40L interaction, CD8+ cytotoxic T lymphocytes, T cell help, CTL priming, CD4+ T helper cells, antigen-presenting cells, costimulation, dendritic cells, macrophages, B cells
- MeSH terms
- Animals, Antigen-Presenting Cells, B-Lymphocytes, Cells, Cultured, T-Lymphocytes, Helper-Inducer, Male, Membrane Glycoproteins, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic, Signal Transduction, Mice, Knockout, CD40 Antigens, CD40 Ligand, Mice
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
