Key Points
-
T lymphocytes can be separated into two subpopulations, based on their expression of CD4 and CD8. The CD4+ subset is primarily responsible for providing help to other immune cells, whereas CD8+ T cells are best known for their capacity to kill virus-infected cells.
-
Cross-presentation is defined as the processing of exogenous antigens into the major histocompatibility complex (MHC) class I pathway. Cross-priming and cross-tolerance refer to the induction of cytotoxic T lymphocyte (CTL) immunity or tolerance, respectively, that is induced by cross-presented antigens.
-
Despite the discovery of cross-priming in the mid-1970s, the antigen-presenting cell responsible for this process has only recently been identified. Bevan and co-workers provided evidence that it is the CD8+ dendritic cell (DC).
-
Although there are several pathways for cross-presentation, our current understanding of which pathway(s) operate in vivo for cross-presentation of cell-associated antigens that are derived from virus-infected cells or self tissues is minimal.
-
As well as providing a mechanism for generating immunity to intracellular infections, cross-presentation has been reported to participate in tolerance induction. Such cross-tolerance is most probably mediated by DCs and leads to the deletion of self-reactive CTLs.
-
Antigen expression levels, the site of expression, the time of expression and the availability of help, crucially determine whether self-antigens cause cross-tolerance.
-
There are few studies that unequivocally show cross-priming to be crucial for natural, protective, CTL immunity. This does not mean that cross-priming has no role in natural immunity, only that it remains difficult to discriminate between the role of cross-presentation and direct presentation in natural CTL priming.
-
Virus-specific CTL immunity has been shown to depend on bone marrow-derived cells (presumably DCs) for several infections, including influenza virus, vaccinia virus, poliovirus and lymphocytic choriomeningitis virus, consistent with a role for cross-priming in viral immunity.
-
One can envisage that cross-priming has an important role in cases where a virus infection is localized to a peripheral non-lymphoid compartment, such as for papilloma virus infection of the epithelial cells of the skin. In addition, cross-priming could be important where viruses have evolved mechanisms that specifically disrupt the immune functions of DCs.
Abstract
T lymphocytes recognize peptide antigens presented by class I and class II molecules encoded by the major histocompatibility complex (MHC). Classical antigen-presentation studies showed that MHC class I molecules present peptides derived from proteins synthesized within the cell, whereas MHC class II molecules present exogenous proteins captured from the environment. Emerging evidence indicates, however, that dendritic cells have a specialized capacity to process exogenous antigens into the MHC class I pathway. This function, known as cross-presentation, provides the immune system with an important mechanism for generating immunity to viruses and tolerance to self.
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
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Miller, B. J., Appel, M. C., O'Neil, J. J. & Wicker, L. S. Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J. Immunol. 140, 52–58 (1988).
Bendelac, A., Carnaud, C., Boitard, C. & Bach, J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J. Exp. Med. 166, 823–832 (1987).
Kurts, C., Kosaka, H., Carbone, F. R., Miller, J. F. & Heath, W. R. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8+ T cells. J. Exp. Med. 186, 239–245 (1997).Provides evidence that self-antigens can be cross-presented and that this leads to deletional tolerance.
Schonrich, G. et al. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 65, 293–304 (1991).
Schonrich, G. et al. Tolerance induction as a multi-step process. Eur. J. Immunol. 24, 285–293 (1994).
Oldstone, M. B., Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319–331 (1991).
Ohashi, P. S. et al. Ablation of 'tolerance' and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–317 (1991).
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).
Bennett, S. R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).
Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).
Salio, M., Cella, M., Suter, M. & Lanzavecchia, A. Inhibition of dendritic cell maturation by herpes simplex virus. Eur. J. Immunol. 29, 3245–3253 (1999).
Servet-Delprat, C. et al. Measles virus induces abnormal differentiation of CD40 ligand-activated human dendritic cells. J. Immunol. 164, 1753–1760 (2000).
Fugier-Vivier, I. et al. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J. Exp. Med. 186, 813–823 (1997).
Gabrilovich, D. I. et al. Murine retrovirus induces defects in the function of dendritic cells at early stages of infection. Cell Immunol. 158, 167–181 (1994).
Ignatius, R. et al. Canarypox virus-induced maturation of dendritic cells is mediated by apoptotic cell death and tumor necrosis factor alpha secretion. J. Virol. 74, 11329–11338 (2000).
Engelmayer, J. et al. Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion. J. Immunol. 163, 6762–6768 (1999).
Sevilla, N. et al. Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J. Exp. Med. 192, 1249–1260 (2000).
Bevan, M. J. Antigen recognition. Class discrimination in the world of immunology. Nature 325, 192–194 (1987).
Bevan, M. J. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J. Exp. Med. 143, 1283–1288 (1976).
Pooley, J. L., Heath, W. R. & Shortman, K. Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8− dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J. Immunol. 166, 5327–5330 (2001).Provides evidence that CD8+ dendritic cells (DCs) are responsible for cross-presentation of soluble ovalbumin. It also shows that CD8−CD4− DCs can cross-present when exposed to lipopolysaccharide.
den Haan, J. M., Lehar, S. M. & Bevan, M. J. CD8+ but not CD8− dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192, 1685–1696 (2000).The first report to show that CD8+ dendritic cells cross-present cell-associated antigens.
Huang, A. Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–965 (1994).
Bennett, S. R., Carbone, F. R., Karamalis, F., Miller, J. F. & Heath, W. R. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J. Exp. Med. 186, 65–70 (1997).
Norbury, C. C., Chambers, B. J., Prescott, A. R., Ljunggren, H. G. & Watts, C. Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells. Eur. J. Immunol. 27, 280–288 (1997).
Regnault, A. et al. Fcγ receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189, 371–380 (1999).
Ke, Y. & Kapp, J. A. Exogenous antigens gain access to the major histocompatibility complex class I processing pathway in B cells by receptor-mediated uptake. J. Exp. Med. 184, 1179–1184 (1996).
Rock, K. L., Gamble, S. & Rothstein, L. Presentation of exogenous antigen with class I major histocompatibility complex molecules. Science 249, 918–921 (1990).
Kovacsovics-Bankowski, M., Clark, K., Benacerraf, B. & Rock, K. L. Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages. Proc. Natl Acad. Sci. USA 90, 4942–4946 (1993).
Albert, M. L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).
Heath, W. R. & Carbone, F. R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).
Carbone, F. R. & Bevan, M. J. Class I-restricted processing and presentation of exogenous cell-associated antigen in vivo. J. Exp. Med. 171, 377–387 (1990).
Vremec, D. et al. The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells. J. Exp. Med. 176, 47–58 (1992).
Kurts, C., Cannarile, M., Klebba, I. & Brocker, T. Dendritic cells are sufficient to cross-present self-antigens to CD8 T cells in vivo. J. Immunol. 166, 1439–1442 (2001).
Yewdell, J. W., Norbury, C. C. & Bennink, J. R. Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: implications for generating CD8+ T cell responses to infectious agents, tumors, transplants, and vaccines. Adv. Immunol. 73, 1–77 (1999).
Yewdell, J. W., Bennink, J. R. & Hosaka, Y. Cells process exogenous proteins for recognition by cytotoxic T lymphocytes. Science 239, 637–640 (1988).
Finelli, A. et al. MHC class I restricted T cell responses to Listeria monocytogenes, an intracellular bacterial pathogen. Immunol. Res. 19, 211–223 (1999).
Schirmbeck, R., Melber, K. & Reimann, J. Hepatitis B virus small surface antigen particles are processed in a novel endosomal pathway for major histocompatibility complex class I-restricted epitope presentation. Eur. J. Immunol. 25, 1063–1070 (1995).
Bachmann, M. F. et al. TAP1-independent loading of class I molecules by exogenous viral proteins. Eur. J. Immunol. 25, 1739–1743 (1995).
Harding, C. V. & Song, R. Phagocytic processing of exogenous particulate antigens by macrophages for presentation by class I MHC molecules. J. Immunol. 153, 4925–4933 (1994).
Srivastava, P. K., Udono, H., Blachere, N. E. & Li, Z. Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39, 93–98 (1994).
Wolfers, J. et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nature Med. 7, 297–303 (2001).
Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nature Med. 4, 594–600 (1998).
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).
Huang, A. Y., Bruce, A. T., Pardoll, D. M. & Levitsky, H. I. In vivo cross-priming of MHC class I-restricted antigens requires the TAP transporter. Immunity 4, 349–355 (1996).
Kurts, C. et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923–930 (1996).First paper to report cross-presentation of tissue antigens and showed this process is constitutive.
Sigal, L. J., Crotty, S., Andino, R. & Rock, K. L. Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen. Nature 398, 77–80 (1999).First paper to provide direct evidence that CTL immunity to viruses could be induced by cross-priming.
Kurts, C., Miller, J. F., Subramaniam, R. M., Carbone, F. R. & Heath, W. R. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J. Exp. Med. 188, 409–414 (1998).Provides the important observation that antigen dose is vital to whether a tissue antigen will be cross-presented. Also shows that tissue damage enhances cross-presentaton.
Bellone, M. et al. Processing of engulfed apoptotic bodies yields T cell epitopes. J. Immunol. 159, 5391–5399 (1997).
Arrode, G. et al. Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infected fibroblasts is cross-presented to CD8+ T cells by dendritic cells. J. Virol. 74, 10018–10024 (2000).
Debrick, J. E., Campbell, P. A. & Staerz, U. D. Macrophages as accessory cells for class I MHC-restricted immune responses. J. Immunol. 147, 2846–2851 (1991).
Huang, F. P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–444 (2000).Shows that gut-associated dendritic cells constitutively capture apoptotic epithelial cells and transport them to the mesenteric lymph node.
Miller, J. F. et al. Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens. Immunol. Rev. 165, 267–277 (1998).
Kurts, C. et al. CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose. Proc. Natl Acad. Sci. USA 96, 12703–12707 (1999).
Morgan, D. J., Kreuwel, H. T. & Sherman, L. A. Antigen concentration and precursor frequency determine the rate of CD8+ T cell tolerance to peripherally expressed antigens. J. Immunol. 163, 723–727 (1999).
Li, M. et al. Cell-associated ovalbumin is cross-presented much more efficiently than soluble ovalbumin in vivo. J. Immunol. 166, 6099–6103 (2001).
Harshyne, L. A., Watkins, S. C., Gambotto, A. & Barratt-Boyes, S. M. Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J. Immunol. 166, 3717–3723 (2001).First paper to show that dendritic cells might capture and cross-present antigens from other cells without killing the donor cells.
von Boehmer, H. & Hafen, K. Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature 320, 626–628 (1986).
Merkenschlager, M., Power, M. O., Pircher, H. & Fisher, A. G. Intrathymic deletion of MHC class I-restricted cytotoxic T cell precursors by constitutive cross-presentation of exogenous antigen. Eur. J. Immunol. 29, 1477–1486 (1999).
Adler, A. J. et al. CD4+ T cell tolerance to parenchymal self antigens requires presentation by bone marrow derived antigen presenting cells. J. Exp. Med. 187, 1555–1564 (1998).
Forster, I. & Lieberam, I. Peripheral tolerance of CD4 T cells following local activation in adolescent mice. Eur. J. Immunol. 26, 3194–3202 (1996).
Hoglund, P. et al. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J. Exp. Med. 189, 331–339 (1999).
Morgan, D. J. et al. Ontogeny of T cell tolerance to peripherally expressed antigens. Proc. Natl Acad. Sci. USA 96, 3854–3858 (1999).
Gooding, L. R. & Edwards, C. B. H-2 antigen requirements in the in vitro induction of SV40-specific cytotoxic T lymphocytes. J. Immunol. 124, 1258–1262 (1980).
Schoenberger, S. P. et al. Cross-priming of CTL responses in vivo does not require antigenic peptides in the endoplasmic reticulum of immunizing cells. J. Immunol. 161, 3808–3812 (1998).
Sigal, L. J. & Rock, K. L. Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation. J. Exp. Med. 192, 1143–1150 (2000).
Lenz, L. L., Butz, E. A. & Bevan, M. J. Requirements for bone marrow-derived antigen-presenting cells in priming cytotoxic T cell responses to intracellular pathogens. J. Exp. Med. 192, 1135–1142 (2000).
Norbury, C. C. et al. Multiple antigen-specific processing pathways for activating naive CD8+ T cells in vivo. J. Immunol. 166, 4355–4362 (2001).
Tindle, R. W. & Frazer, I. H. Immune response to human papillomaviruses and the prospects for human papillomavirus-specific immunisation. Curr. Top. Microbiol. Immunol. 186, 217–253 (1994).
Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).
Hill, A. et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature 375, 411–415 (1995).
Ahn, K. et al. Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proc. Natl Acad. Sci. USA 93, 10990–10995 (1996).
Fruh, K. et al. A viral inhibitor of peptide transporters for antigen presentation. Nature 375, 415–418 (1995).
Gilbert, M. J., Riddell, S. R., Plachter, B. & Greenberg, P. D. Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Nature 383, 720–722 (1996).
Levitskaya, J., Sharipo, A., Leonchiks, A., Ciechanover, A. & Masucci, M. G. Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc. Natl Acad. Sci. USA 94, 12616–12621 (1997).
Paabo, S. et al. Adenovirus proteins and MHC expression. Adv. Cancer Res. 52, 151–163 (1989).
Ronchetti, A. et al. Immunogenicity of apoptotic cells in vivo: role of antigen load, antigen-presenting cells, and cytokines. J. Immunol. 163, 130–136 (1999).
Chiodoni, C. et al. Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. J. Exp. Med. 190, 125–133 (1999).
Kundig, T. M. et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science 268, 1343–1347 (1995).
Ochsenbein, A. F. et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411, 1058–1064 (2001).
Vremec, D., Pooley, J., Hochrein, H., Wu, L. & Shortman, K. CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J. Immunol. 164, 2978–2986 (2000).
Kamath, A. T. et al. The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J. Immunol. 165, 6762–6770 (2000).
De Smedt, T. et al. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J. Exp. Med. 184, 1413–1424 (1996).
Pulendran, B. et al. Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice. J. Immunol. 159, 2222–2231 (1997).
Acknowledgements
The authors thank several people for their suggestions upon reading drafts of this manuscript, including Dr G. Davey, Dr G. Belz, Dr J. Villadangos, Dr. G. Behrens, Ms J. Mintern, Ms M. Li and Dr M. Bevan.
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
Glossary
- ISOTYPE SWITCHING
-
When B cells change their class of antibody (immunoglobulin) production from one isotype to another, for example from IgM to IgG.
- THYMIC SELECTION
-
The process of choosing which thymocytes develop into mature T cells on the basis of the specificity of their T-cell receptors.
- PERIPHERAL TOLERANCE
-
The generation of tolerance to self for mature T cells that have left the thymus and are recirculating in the periphery.
- CENTRAL TOLERANCE
-
The generation of tolerance to self during T-cell development in the thymus.
- ALLOGENEIC
-
Individuals within a species that express allelically variant genes that lead to rejection of transplanted tissue.
Rights and permissions
About this article
Cite this article
Heath, W., Carbone, F. Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 1, 126–134 (2001). https://doi.org/10.1038/35100512
Issue Date:
DOI: https://doi.org/10.1038/35100512
This article is cited by
-
Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers
Journal of Nanobiotechnology (2021)
-
TAP dysfunction in dendritic cells enables noncanonical cross-presentation for T cell priming
Nature Immunology (2021)
-
Inducing immune tolerance with dendritic cell-targeting nanomedicines
Nature Nanotechnology (2021)
-
Effect of asbestos exposure on differentiation and function of cytotoxic T lymphocytes
Environmental Health and Preventive Medicine (2020)
-
Engineering universal cells that evade immune detection
Nature Reviews Immunology (2019)