Key Points
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Cross-presentation allows dendritic cells (DCs) to activate CD8+ cytotoxic T lymphocytes (CTLs) for immune defence against viruses that do not infect DCs and tumours that originate from non-DCs.
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Immunogenic cross-presentation (cross-priming) requires that DCs are licensed by T helper (TH) cells or natural killer T (NKT) cells, which renders them competent to programme CTLs for survival, effector function and memory cell generation.
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Licensing TH or NKT cells cause DCs to produce discrete chemokines that recruit naive CTLs into lymphatic tissues for cross-priming. Also, DC–TH cell interaction in non-lymphatic tissues results in chemokine production that recruits cross-primed CTLs for cytotoxic effector functions, which promote antiviral defence and immune-mediated disease.
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Cross-priming allows for the expansion of CTLs and the induction of antiviral immunity even in the presence of viral immune escape from MHC class I presentation in infected cells
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Cross-presentation of autoantigens causes deletion of autoreactive CTLs that have escaped central tolerance; failure of such cross-tolerance is thought to contribute to the pathogenesis of autoimmune diseases, such as type 1 diabetes, multiple sclerosis and psoriasis.
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Many tumour antigens are effectively cross-presented but this rarely results in effective cross-priming. Vaccination strategies that combine tumour antigens with adjuvants that mature DCs and increase cross-presentation and chemokine production may overcome this problem when combined with suitable chemotherapies that do not compromise antitumour immunity.
Abstract
Cross-priming is an important mechanism to activate cytotoxic T lymphocytes (CTLs) for immune defence against viruses and tumours. Although it was discovered more than 25 years ago, we have only recently gained insight into the underlying cellular and molecular mechanisms, and we are just beginning to understand its physiological importance in health and disease. Here we summarize current concepts on the cross-talk between the immune cells involved in CTL cross-priming and on its role in antimicrobial and antitumour defence, as well as in immune-mediated diseases.
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Acknowledgements
The authors thank W. Kolanus (LIMES Institute Bonn), J. Yewdell (NIH), M. von Herrath (LIAI) and R. Slattery (Monash University Melbourne) for comments and discussions. We apologize to all colleagues whose work could not be cited owing to space restrictions. The authors are supported by the German Research foundation (DFG Sonderforschungsbereiche 704, 670 and 645, Transregio 57, Klinische Forschergruppe 228), the German Academic Exchange service (DAAD) and the Group of Eight, Australia.
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Glossary
- Cross-presentation
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The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation can lead to cross-priming or cross-tolerance.
- Cross-priming
-
The initiation of an immunogenic CD8+ T cell response to an antigen that is not synthesized by the antigen-presenting cell. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.
- Cross-tolerance
-
The antigen-specific tolerization of CD8+ T cells by antigen-presenting cells that cross-present self or innocuous antigens, which results in BIM-mediated (BCL-2 inhibitable) deletion of autoreactive CD8+ T cells.
- C-type lectin receptors
-
A large family of receptors that bind glycosylated ligands and have several roles, such as in cell adhesion, endocytosis, pathogen recognition, natural killer cell target recognition and dendritic cell activation.
- Inflammasome
-
A large multiprotein complex formed by a nucleotide-binding domain (NBD)-, leucine-rich repeat (LRR)-containing family (NLR) protein, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase 1. The assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-IL-1β and pro-IL-18 to generate the active pro-inflammatory cytokines.
- DC licensing
-
A concept that DCs must be converted by an antigen-specific T helper cell into a functional state required for immunogenic activation of CTLs, which decreases the likelihood of autoimmunity, but requires coordination of cell encounters by chemokines.
- CTL programming
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A concept that CTLs receive additional information during their activation that affects their effector functions, life-span, memory differentiation or migratory properties. These signals determine whether cross-presentation leads to cross-priming or cross-tolerance.
- Central tolerance
-
Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus and B cells in the bone marrow that strongly recognize self antigen face deletion or marked suppression.
- Antigenic mimicry
-
A mechanism for the induction of autoimmunity, in which a pathogen expresses a protein or peptide that is similar to a self protein. After the induction of a pathogen-specific immune response, a cross-reactive response to self results in autoimmune pathology.
- Oligodendrocyte
-
A type of glial cell that creates the myelin sheath that insulates axons and improves the speed and reliability of signal transmission by neurons.
- Signals 1 and 2
-
T cells require presentation of antigen (signal 1) and co-stimulatory signals (signal 2) for immunogenic activation; cytokines have been proposed to be a third signal that dictates T cell differentiation.
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Kurts, C., Robinson, B. & Knolle, P. Cross-priming in health and disease. Nat Rev Immunol 10, 403–414 (2010). https://doi.org/10.1038/nri2780
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DOI: https://doi.org/10.1038/nri2780
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