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The term cross-presentation (or cross-priming) denotes 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). This process is necessary for immunity against most tumors and against viruses that do not infect antigen-presenting cells.[1][2]

It is also required for induction of cytotoxic immunity by vaccination with protein antigens, for example in tumor vaccination.[3]


The first evidence of cross-presentation was reported 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”.[4]

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.[5]

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,..), bacteria (Listeria, Salmonella, E.coli,…) and tumors (Brain, pancreas, melanoma, leukemia,..).[6][7]

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

Also 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.[8]

Cell biology

Antigen-presenting cells capable of cross-presentation are primarily dendritic cells,[9][10] but also macrophages, B lymphocytes and liver sinusoidal endothelial cells have 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.[11][12]

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, where they associate with MHC class I molecules. [13][11]

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

Role of CD4 T cell help

There is currently much debate over the role of CD4 T cell help for the CD8 T cell response. It is thought that vigorous CD8 T cell responses and the generation and maintenance of CD8 T cell memory require help by CD4 T cells.[14]

These stimulate dendritic cells by the cell surface molecule CD40 ligand, or directly stimulate CD8 T cells by cytokines such as Interleukin-2.[1]

In the absence of such help, CD8 T cells die upon secondary encounter with antigen.[15]

The involvement of CD4 T helper cells implies that the AIDS virus indirectly compromises antiviral CD8 T cell responses, and may thereby escape immune defense.


  1. 1.0 1.1 Heath WR, Carbone FR. 2001. Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 1: 126-34
  2. Rock KL. 1996. A new foreign policy: MHC class I molecules monitor the outside world. Immunol. Today 17: 131-7
  3. 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
  4. 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
  5. Wolkers MC, Brouwenstijn N, Bakker AH, Toebes M, Schumacher TN. 2004. Antigen bias in T cell cross-priming. Science 304: 1314-7
  6. 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
  7. 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
  8. Kurts C, H Kosaka, FR Carbone, JFAP Miller und WR Heath. 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
  9. 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.
  10. 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.
  11. 11.0 11.1 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
  12. 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
  13. Cresswell P, Bangia N, Dick T, Diedrich G. 1999. The nature of the MHC class I peptide loading complex. Immunol Rev 172: 21-8
  14. Bevan MJ. 2004. Helping the CD8(+) T-cell response. Nat Rev Immunol 4: 595-602
  15. Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. 2003. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421: 852-6

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