Cross-presentation

Cross-presentation is the ability of certain antigen-presenting cells to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the naive cytotoxic CD8+ T cell stimulation.[1] This process is necessary for immunity against most tumors and against viruses that do not readily infect antigen-presenting cells, or impair dendritic cell normal function .[2][3] It is also required for induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.[4]

Cross-presentation is of particular importance, because it permits the presentation of exogenous antigens, which are normally presented by MHC II on the surface of infected dendritic cells to be also presented by MHC I without infecting the dendritic cell. Cross-presentation allows the dendritic cell to avoid using the endogenous proteasomal processing pathway, which otherwise would divert cellular resources away from MHC II presentation processes that present exogenous antigens after infection. Such a diversion could functionally impair the dendritic cell.[5]

History

The first evidence of cross-presentation was reported in 1976 by Michael J. Bevan after injection of cells carrying alloantigens into experimental animals. This resulted in CD8 T cell responses that were induced by antigen-presenting cells of the recipient, implying that these must have taken up and processed the injected cells. This observation was termed “cross-priming”.[6]

Later, there had been much controversy about cross-presentation, which now is believed to have been due to particularities and limitations of some experimental systems used.[7]

Relevance for immunity

Cross-presentation has been shown to play a role in the immune defense against many viruses (herpesvirus, influenzavirus, CMV, EBV, SIV, papillomavirus, and others), bacteria (listeria, salmonella, E. coli, M. tuberculosis, and others) and tumors (brain, pancreas, melanoma, leukemia, and others).[8][9]

Cross-priming avoids viral immune evasion strategies, such as suppression of antigen processing. Consequently, immune responses against viruses that are able to do so, such as herpes viruses, are largely dependent on cross-presentation.

Relevance for immune tolerance

Some self-antigens (autoantigens) are cross-presented, resulting in the elimination of autoreactive CD8 T cells. This mechanism to maintain self tolerance has been termed cross-tolerance.[10]

Cell biology

Antigen-presenting cells capable of cross-presentation are primarily dendritic cells,[11][12] but macrophages, B lymphocytes and sinusoidal endothelial cells have also been shown to be able to do so. The intracellular mechanisms of cross-presentation are still unclear, but seem to involve specialized subcellular compartments bearing characteristics of both the endoplasmic reticulum and the endosome.[13][14]

Endocytosed proteins are transported out of this compartment into the cytoplasm by unknown mechanisms. There they are processed by the proteasome into peptides, which are transported by the TAP transporter into the endoplasmic reticulum,[13][15] or back into the same endosomes,[16] where they associate with MHC I. In addition to solid structure uptake, dendritic cell phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross-presentation pathway.[17]

According to another study (done by some of the same people cited at the bottom of paragraph 1 of this section), as the phagosome forms or soon after it forms, it fuses with the ER to form an ER-phagosome mix compartment. The ATP-dependent TAP of the phagosomal compartment (at some stage of its lifecycle) transports the antigens out to the cytosol for proteasomal degradation and back into the compartment for loading onto MHC I. This mix compartment set-up helps the cell tolerate the scarcity of antigens in the relatively large cytoplasm for cross-presentation.[18]

Finally, MHC class I-peptide complexes are transported to the cell surface, where they can be detected by specific CD8 T cells.

Cytosolic Diversion

There is evidence that suggest that cross-presentation requires cytosolic diversion in a proportion of CD8(+) dendritic cells that are able to cross-present.[19]

In the capable dendritic cells, cytosolic diversion is the name of the process that diverts antigens away from the route in which they are guided for antigen presentation by MHC II by being transported for release into the cytoplasm following endocytosis for degradation by the proteasomes necessary for MHC I antigen presentation (cross-presentation).[5]

There is evidence that phagosome-to-cytosol diversion (cytolic diversion) of endocytosed ovalbumin antigens (OVA) occur in Archaea, after which classical antigen processing for presentation by MHC I occurs. The process of endocytosis and cross-presentation (involving cytosolic diversion) can be enhanced by the addition of an adjuvant in the form of isoprenoid glycerolipid vesicles named archaeosomes and filled with the antigens. The adjuvant is recognized by phosphatidylserine receptors. [20]

References

  1. ↑ Bevan, Michael J. (2006). "Cross-priming". Nature Immunology (Nature Publishing Group) 7 (4): 363–5. doi:10.1038/ni0406-363. PMID 16550200.
  2. ↑ Heath, WR; Carbone, FR (2001). "Cross-presentation in viral immunity and self-tolerance". Nat Rev Immunol 1: 126–34. doi:10.1038/35100512.
  3. ↑ Rock, KL (1996). "A new foreign policy: MHC class I molecules monitor the outside world". Immunol. Today 17: 131–7. doi:10.1016/0167-5699(96)80605-0.
  4. ↑ Melief, CJ (2003). "Mini-review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming?". Eur J Immunol 33: 2645–54. doi:10.1002/eji.200324341.
  5. 1 2 William R. Heath & Francis R. Carbone (November 2001). "Cross-presentation in viral immunity and self-tolerance". Nature Reviews Immunology 1 (2): 126–134. doi:10.1038/35100512. Retrieved 28 April 2013.
  6. ↑ Bevan, MJ (1976). "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: 1283–8. doi:10.1084/jem.143.5.1283.
  7. ↑ Wolkers, MC; Brouwenstijn, N; Bakker, AH; Toebes, M; Schumacher, TN (2004). "Antigen bias in T cell cross-priming". Science 304: 1314–7. doi:10.1126/science.1096268.
  8. ↑ Huang, AY; Golumbek, P; Ahmadzadeh, M; Jaffee, E; Pardoll, D; Levitsky, H (1994). "Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens". Science 264: 961–5. doi:10.1126/science.7513904.
  9. ↑ Sigal, LJ; Crotty, S; Andino, R; Rock, KL (1999). "Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen". Nature 398: 77–80. doi:10.1038/18038.
  10. ↑ Kurts, C; Kosaka, H; Carbone, FR; Miller, JFAP; Heath, WR (1997). "Exogenous class I-restricted cross-presentation of self antigens can lead to deletion of autoreactive CD8+ T cells". J Exp Med 186: 239–245. doi:10.1084/jem.186.2.239. PMC 2198972. PMID 9221753.
  11. ↑ den Haan, JM; Lehar, SM; Bevan, MJ (2000). "CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo". J Exp Med 192: 1685–96. doi:10.1084/jem.192.12.1685.
  12. ↑ Kurts, C; Cannarile, M; Klebba, I; Brocker, T (2001). "Dendritic cells are sufficient to cross-present self-antigens to CD8 T cells in vivo". J Immunol 166: 1439–42. doi:10.4049/jimmunol.166.3.1439.
  13. 1 2 Guermonprez, P; Saveanu, L; Kleijmeer, M; Davoust, J; Van Endert, P; Amigorena, S (2003). "ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells". Nature 425: 397–402. doi:10.1038/nature01911.
  14. ↑ Burgdorf, S; Kautz, A; Böhnert, V; Knolle, PA; Kurts, C (2007). "Distinct antigen uptake and intracellular routing mechanisms in CD4 and CD8 T cell activation". Science 316: 612–6. doi:10.1126/science.1137971.
  15. ↑ Cresswell, P; Bangia, N; Dick, T; Diedrich, G (1999). "The nature of the MHC class I peptide loading complex". Immunol Rev 172: 21–8. doi:10.1111/j.1600-065x.1999.tb01353.x.
  16. ↑ Burgdorf, S; Schölz, C; Kautz, A; Tampé, R; Kurts, C (2008). "Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation". Nature Immunol 9: 558–566. doi:10.1038/ni.1601.
  17. ↑ Hari, A; Ganguly, A; Mu, L; Davis, SP; Stenner, MD; et al. (2014). "Redirecting soluble antigen for MHC class I cross-presentation during phagocytosis.". Eur J Immunol. 45: 383–95. doi:10.1002/eji.201445156. PMID 25378230.
  18. ↑ Pierre Guermonprez, Loredana Saveanu, Monique Kleijmeer, Jean Davoust, Peter van Endert, Sebastian Amigorena (25 September 2003). "ER–phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells". Nature 425 (6956): 397–402. doi:10.1038/nature01911.
  19. ↑ Lin ML, Zhan Y, Proietto AI, Prato S, Wu L, Heath WR, Villadangos JA, Lew AM (Feb 26, 2008). "Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset". Proc Natl Acad Sci U S A 105 (8): 3029–3034. doi:10.1073/pnas.0712394105. PMC 2268579. PMID 18272486.
  20. ↑ Gurnani K, Kennedy J, Sad S, Sprott GD, Krishnan L. (Jul 2004). "Phosphatidylserine receptor-mediated recognition of archaeosome adjuvant promotes endocytosis and MHC class I cross-presentation of the entrapped antigen by phagosome-to-cytosol transport and classical processingjournal=J Immunol.". J Immunol 173 (1): 566–578. doi:10.4049/jimmunol.173.1.566. PMID 15210818.

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