Abstract
We show here that priming and memory generation of antigen-specific CD8+ cytotoxic T lymphocytes (CTL) does not require help if the immunogen binds major histocompatibility complex (MHC) class I molecules with high affinity. This conclusion was based on the study of three chemically distinct optimal length CTL epitopes with high affinity for the restriction element Kb. In contrast, when two subdominant epitopes with intermediate MHC binding affinity were studied, either a class II MHC–restricted T helper cell epitope or administration of antibody to CD40 was required to obtain significant CTL priming. Depending on the epitope, one source of help was much more efficient than the other.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Henkart, P.A. Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules . Immunity 1, 343–346 (1994).
Yewdell, J.W. & Bennink, J.R. in Clinical Virology (eds Richman, D.D., Whitely, R.J. & Hayden, F.G.) (Churchill Livingstone, 1995).
Markiewicz, M.A. & Gajewski, T.F. The immune system as anti-tumor sentinel: molecular requirements for an anti-tumor immune response. Crit. Rev. Oncog. 10, 247– 260 (1999).
Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272 , 54–60 (1996).
O'Rourke, A.M. & Mesher, M.F. Cytotoxic T-lymphocyte activation involves a cascade of signalling and adhesion events. Nature. 358, 253–255 (1992).
Bachmann, M.F. et al. Distinct roles for LFA-1 and CD28 during activation of naïve T cells: adhesion versus costimulation. Immunity 7, 549–557 (1997).
Cai, Z. et al. Transfected Drosophila cells as a probe for defining the minimal requirements for stimulating unprimed CD8+ T cells. Proc. Natl Acad. Sci. USA 93, 14736– 14741 (1996).
Bhardwaj, N. et al. Influenza virus infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells . J. Clin. Invest. 94, 797– 807 (1994).
Bachmann, M.F. et al. Dendritic cells process exogenous viral proteins and virus-like particles for class I presentation to CD8+ cytotoxic T lymphocytes . Eur. J. Immunol. 26, 2595– 2600 (1996).
Keene, J. A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 ( 1982).
Simpson, E. & Gordon, R.D. Responsiveness to H-Y antigen. Ir-gene complementation and target specificity. Immunol Rev. 35, 59–75 (1997).
Ridge, J.P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 ( 1998).
Schoenberger, S.P., Toes, R.E.M., van der Voort, E.I.H., Offringa, R. & Melief, C.J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).
Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling . Nature 393, 478–480 (1998).
Buller, R.M., Holmes, K.L., Hugin. A., Frederickson, T.N. & Morse, H.C. Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328 , 77–79 (1987).
Tripp, R.A., Sarawar, S.R. & Doherty, P.C. Characteristics of the influenza virus-specific CD8+ T cell response in mice homozygous for disruption of the H-21Ab Iab gene. J. Immunol. 155, 2955 –2959 (1995).
Aichele, P., Hengartner, H., Zinkernagel, R.M. & Schulz, M. Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide. J. Exp. Med. 171, 1815–1820 (1990).
Kast, W.M. et al. Protection against lethal Sendai virus infection by in vivo priming of virus-specific cytotoxic T lymphocytes with a free synthetic peptide. Proc. Natl Acad. Sci. USA 88, 2283 –2287 (1991).
Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693– 1702 (1992).
Niedermann, G. et al. Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules . Immunity 2, 289–299. (1995).
van der Most, R.G. et al. Identification of Db- and Kb- restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice. Virology 240, 158– 167 (1998).
Pilarski, L.M. A requirement for antigen-specific helper T cells in the generation of cytotoxic T cells from thymocyte precursors. J. Exp. Med. 145 , 709–725 (1977).
Cooley, M.A. & Schmitt-Verhulst, A.M. Specific helper T cells permit differentiation of thymic anti-self-trinitrophenyl cytotoxic precursor cells. J. Immunol. 123, 2328– 2336 (1979).
Finberg, R., Burakoff, S.J., Benacerraf, B. & Greene, M.I. The cytolytic T lymphocyte response to trinitrophenyl-modified syngeneic cells. II. Evidence for antigen-specific suppressor T cells. J. Immunol. 123, 1210–1214 ( 1979).
Zinkernagel, R.M. et al. The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help. J. Exp. Med. 147, 897–911 (1978).
Cardin, R.D., Brooks, J.W., Sarawar, S.R. & Doherty, P.C. Progressive loss of CD8+ T cell-mediated control of a γ-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184, 863–871 (1996).
Lu, Z. et al. CD40-independent pathways of T cell help for priming of CD8+ cytotoxic T lymphocytes. J. Exp. Med. 191 , 541–550 (2000).
Schaeffer, E.B. et al. Relative contribution of “determinant selection” and “holes in the T cell repertoire” to T-cell responses. Proc. Natl Acad. Sci. USA 86, 4649– 4653 (1989).
Sette, A. et al. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J. Immunol. 153, 5586–5592 (1994).
Rock, K.L. & Clark, K. Analysis of the role of MHC class II presentation in the stimulation of cytotoxic T lymphocytes by antigens targeted into the endogenous antigen-MHC class I presentation pathway. J. Immunol. 156, 3721–3726 (1996).
Ruedl, C.M., Kopf, M.F. & Bachmann, M.F. CD8+ T cells mediate CD40-independent maturation of dendritic cells in vivo. J. Exp. Med. 189, 1875–1884 (1999).
Maltubian, M., Concepcion, R.J. & Ahmed, R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection . J. Virol. 68, 8056–8063 (1994).
von Herrath, M.G., Yokoyama, M., Dockter, J., Oldstone, M.B. & Whitton, J.L. CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. J. Virol. 70, 1072–1079 (1996).
Sauzet, J.P., Gras-Masse, H., Guillet, J.G. & Gomard, E. Influence of strong CD4 epitope on long-term virus-specific cytotoxic T cell responses induced in vivo with peptides. Int. Immunol. 8, 457–465 (1996).
Di Rosa, F. & Matzinger, P. Long-lasting CD8 T cell memory in the absence of CD4 T cells or B cells. J. Exp. Med. 183, 2153–2163 (1996).
Tanchot, C., Lemonnier, F.A., Perarnau, B., Freitas, A.A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naïve or memory T cells. Science 276, 2057–2062 ( 1997).
Borrow, P. et al. CD40 ligand-mediated interactions are involved in the generation of memory CD8(+) cytotoxic T lymphocytes (CTL) but are not required for the maintenance of CTL memory following virus infection. J. Virol. 72, 7440–7449 ( 1998).
Rock, K.L., Benacerraf, B. & Abbas, A.K. Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. J. Exp. Med. 160, 1102–1113. (1984).
Barnaba, V., Franco, A., Alberti, A., Benvenuto, R. & Balsano, F. Selective killing of hepatitis B envelope antigen-specific B cells by class I-restricted, exogenous antigen-specific T lymphocytes. Nature 345, 258–260 ( 1990).
Chan, O.T. & Shlomchik, M.J. Cutting edge: B cells promote CD8+ T cell activation in MRL-Fas(lpr) mice independently of MHC class I antigen presentation. J. Immunol. 164, 1658–1662 (2000).
Tough, D.F., Borrow, P. & Sprent, J. Induction of bystander T cell proliferation by viruses and type 1 Interferon in vivo. Science 272, 1947–1950 (1996).
Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity. 8, 177–187 (1998).
St. Hilaire, P.M. et al. Synthesis of T-antigen containing glycopeptides as potential cancer vaccines. J. Chem. Soc. 1, 3559– 3564 (1999).
Franco, A. et al. Fine specificity and MHC restriction of trinitrophenyl-specific CTL. J. Immunol. 162, 3388– 3394 (1999).
Springer, G.F. T and Tn, general carcinoma autoantigens. Science. 224, 1198–1206 (1984).
Van Bleek, G.M.V. & Nathenson, S.G. Isolation of an endogenously processed immuno-dominant viral peptide from the class I H-2Kb molecule. Nature 348, 213–216 (1990).
Sette, A. et al. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Mol. Immunol. 31, 813–822. (1994).
Franco, A., Guidotti, L., Hobbs, M.V., Pasquetto, V. & Chisari, F.V. Pathogenetic effector function of CD4+ T helper 1 cells in hepatitis B virus transgenic mice . J. Immunol. 159, 2001– 2008 (1997).
Acknowledgements
We thank V. Barnaba and G. Ishioka for discussions, S. Schoenberger for mAb to CD40, A. Sette and J. Sidney for Kb binding analysis of the two subdominant epitopes, M.R. Ullah for peptide synthesis, Y. Wang-Zhu for the CTLL-2 cell line, D. O'Masters for animal care assistance and J. Joseph for assistance in manuscript preparation. Supported by grants from the National Institutes of Health (to A.F. and H.G.). This is manuscript no.369 from the La Jolla Institute for Allergy and Immunology.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Franco, A., Tilly, D., Gramaglia, I. et al. Epitope affinity for MHC class I determines helper requirement for CTL priming. Nat Immunol 1, 145–150 (2000). https://doi.org/10.1038/77827
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/77827
This article is cited by
-
Evaluation of MHC class I peptide binding prediction servers: Applications for vaccine research
BMC Immunology (2008)
-
The role of CD4+ T cell help in cancer immunity and the formulation of novel cancer vaccines
Cancer Immunology, Immunotherapy (2006)
-
Importance of CD4+ Helper T-cells in Antitumor Immunity
International Journal of Hematology (2003)
-
IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages
Nature Medicine (2002)
-
HER2 peptide-specific CD8+ T cells are proportionally detectable long after multiple DNA vaccinations
Gene Therapy (2002)