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  • Review Article
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Cross-presentation in viral immunity and self-tolerance

Nature Reviews Immunology volume 1, pages 126–134 (2001)Cite this article

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.

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Figure 1: Different antigen-processing pathways for the MHC class I and class II molecules.
Figure 2: Licensing of dendritic cells is required for the generation of CTL immunity.
Figure 3: Monkey dendritic cells (DCs) acquire labelled plasma membrane from other live monkey DCs.
Figure 4: Cross-presentation of self-antigens leads to induction of CTL tolerance to peripheral tissues.
Figure 5: Viral subversion of dendritic cell function: cross-priming is required to generate CTL immunity.

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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.

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Authors and Affiliations

  1. Immunology Division, The Walter and Eliza Hall Institute, P.O. Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia

    William R. Heath

  2. Department of Microbiology and Immunology, University of Melbourne, Parkville, 3052, Victoria, Australia

    Francis R. Carbone

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  1. William R. Heath
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Correspondence to William R. Heath.

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DATABASES

LocusLink

CD4

CD8

CD40

CD40L

CLIP

GM-CSF

Herpes simplex virus

Measles virus

TAP

Vaccinia virus

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.

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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

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