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Cross-priming in health and disease

Nature Reviews Immunology volume 10, pages 403–414 (2010)Cite this article

Subjects

Key Points

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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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Figure 1: Molecular mechanisms of licensing dendritic cells for classical cross-priming.
Figure 2: Recruitment of cross-primed effector cytotoxic T lymphocytes into non-lymphoid tissues.
Figure 3: Cross-priming and immunotherapy in an effective antitumour immune response.

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References

  1. 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). This is a seminal paper describing the phenomenon of cross-priming.

    Article  CAS  PubMed  Google Scholar 

  2. Huang, A. Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–965 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. Yewdell, J. W. & Haeryfar, S. M. Understanding presentation of viral antigens to CD8+ T cells in vivo: the key to rational vaccine design. Annu. Rev. Immunol. 23, 651–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. 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). This paper showed the phenomenon of cross-tolerance in a transgenic model, in which cross-presentation of autoantigen causes peripheral deletion of autoreactive CTLs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shortman, K. & Naik, S. H. Steady-state and inflammatory dendritic-cell development. Nature Rev. Immunol. 7, 19–30 (2007).

    Article  CAS  Google Scholar 

  7. Heath, W. R. & Carbone, F. R. Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nature Immunol. 10, 1237–1244 (2009).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. del Rio, M. L., Rodriguez-Barbosa, J. I., Kremmer, E. & Forster, R. CD103− and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells. J. Immunol. 178, 6861–6866 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nature Immunol. 10, 488–495 (2009).

    Article  CAS  Google Scholar 

  12. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. den Haan, J. M. & Bevan, M. J. Constitutive versus activation-dependent cross-presentation of immune complexes by CD8+ and CD8− dendritic cells in vivo. J. Exp. Med. 196, 817–827 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chung, Y., Chang, J. H., Kweon, M. N., Rennert, P. D. & Kang, C. Y. CD8α−11b+ dendritic cells but not CD8α+ dendritic cells mediate cross-tolerance toward intestinal antigens. Blood 106, 201–206 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Lutz, M. B. & Kurts, C. Induction of peripheral CD4+ T-cell tolerance and CD8+ T-cell cross-tolerance by dendritic cells. Eur. J. Immunol. 39, 2325–2330 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Ballesteros-Tato, A., Leon, B., Lund, F. E. & Randall, T. D. Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+ T cell responses to influenza. Nature Immunol. 11, 216–224 (2010).

    Article  CAS  Google Scholar 

  18. McDonnell, A. M., Prosser, A. C., van Bruggen, I., Robinson, B. W. & Currie, A. J. CD8α+ DC are not the sole subset cross-presenting cell-associated tumor antigens from a solid tumor. Eur. J. Immunol. 1 Apr 2010 (doi:10.1002/eji.200940153).

    Article  CAS  PubMed  Google Scholar 

  19. Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Saveanu, L. et al. IRAP identifies an endosomal compartment required for MHC class I cross-presentation. Science 325, 213–217 (2009).

    CAS  PubMed  Google Scholar 

  21. Burgdorf, S., Kautz, A., Bohnert, V., Knolle, P. A. & Kurts, C. Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science 316, 612–616 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Burgdorf, S. & Kurts, C. Endocytosis mechanisms and the cell biology of antigen presentation. Curr. Opin. Immunol. 20, 89–95 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Caminschi, I. et al. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood 112, 3264–3273 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Weck, M. M. et al. hDectin-1 is involved in uptake and cross-presentation of cellular antigens. Blood 111, 4264–4272 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Medema, J. P. et al. Expression of the serpin serine protease inhibitor 6 protects dendritic cells from cytotoxic T lymphocyte-induced apoptosis: differential modulation by T helper type 1 and type 2 cells. J. Exp. Med. 194, 657–667 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bocharov, G., Ford, N. J. & Ludewig, B. A mathematical approach for optimizing dendritic cell-based immunotherapy. Methods Mol. Med. 109, 19–34 (2005).

    CAS  PubMed  Google Scholar 

  27. van Stipdonk, M. J., Lemmens, E. E. & Schoenberger, S. P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nature Immunol. 2, 423–429 (2001).

    Article  CAS  Google Scholar 

  28. Kaech, S. M. & Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nature Immunol. 2, 415–422 (2001).

    Article  CAS  Google Scholar 

  29. Allan, R. S. et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25, 153–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Backer, R. et al. Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells. Proc. Natl Acad. Sci. USA 107, 216–221 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Carbone, F. R., Kurts, C., Bennett, S. R., Miller, J. F. & Heath, W. R. Cross-presentation: a general mechanism for CTL immunity and tolerance. Immunol. Today 19, 368–373 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Heit, A. et al. CpG-DNA aided cross-priming by cross-presenting B cells. J. Immunol. 172, 1501–1507 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Bennett, S. R., Carbone, F. R., Toy, T., Miller, J. F. & Heath, W. R. B cells directly tolerize CD8+ T cells. J. Exp. Med. 188, 1977–1983 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Limmer, A. et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nature Med. 6, 1348–1354 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Steinman, R. M. & Pope, M. Exploiting dendritic cells to improve vaccine efficacy. J. Clin. Invest. 109, 1519–1526 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Maurer, T. et al. CpG-DNA aided cross-presentation of soluble antigens by dendritic cells. Eur. J. Immunol. 32, 2356–2364 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Schulz, O. et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Burgdorf, S., Scholz, C., Kautz, A., Tampe, R. & Kurts, C. Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation. Nature Immunol. 9, 558–566 (2008).

    Article  CAS  Google Scholar 

  39. van Kooyk, Y. & Rabinovich, G. A. Protein-glycan interactions in the control of innate and adaptive immune responses. Nature Immunol. 9, 593–601 (2008).

    Article  CAS  Google Scholar 

  40. Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Barchet, W., Wimmenauer, V., Schlee, M. & Hartmann, G. Accessing the therapeutic potential of immunostimulatory nucleic acids. Curr. Opin. Immunol. 20, 389–395 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Latz, E. The inflammasomes: mechanisms of activation and function. Curr. Opin. Immunol. 22, 28–23 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Hamilton-Williams, E. E. et al. Cutting edge: TLR ligands are not sufficient to break cross-tolerance to self-antigens. J. Immunol. 174, 1159–1163 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Qiu, F. & Cui, Z. CD4+ T helper cell response is required for memory in CD8+ T lymphocytes induced by a poly(I:C)-adjuvanted MHC I-restricted peptide epitope. J. Immunother. 30, 180–189 (2007).

    Article  PubMed  Google Scholar 

  47. Melief, C. J. Mini-review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur. J. Immunol. 33, 2645–2654 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Redmond, W. L. & Sherman, L. A. Peripheral tolerance of CD8 T lymphocytes. Immunity 22, 275–284 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Heymann, F. et al. Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury. J. Clin. Invest. 119, 1286–1297 (2009). This report shows that cross-talk between DCs and autoreactive T H cells in non-lymphoid tissues causes chemokine production and recruitment of cross-primed autoreactive CTLs that cause immunopathology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Smith, C. M. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nature Immunol. 5, 1143–1148 (2004). This paper formally showed that T cells can license DCs for cross-priming of CTLs.

    Article  CAS  Google Scholar 

  52. van Mierlo, G. J. et al. Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication. J. Immunol. 173, 6753–6759 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Sun, J. C., Williams, M. A. & Bevan, M. J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nature Immunol. 5, 927–933 (2004).

    Article  CAS  Google Scholar 

  54. Zehn, D., Lee, S. Y. & Bevan, M. J. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Belz, G. T., Bedoui, S., Kupresanin, F., Carbone, F. R. & Heath, W. R. Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells. Nature Immunol. 8, 1060–1066 (2007).

    Article  CAS  Google Scholar 

  56. Keller, A. M., Xiao, Y., Peperzak, V., Naik, S. H. & Borst, J. Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting. Blood 113, 5167–5175 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Keir, M. E., Freeman, G. J. & Sharpe, A. H. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J. Immunol. 179, 5064–5070 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Mescher, M. F. et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 211, 81–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Williams, M. A., Tyznik, A. J. & Bevan, M. J. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441, 890–893 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Spierings, D. C., Lemmens, E. E., Grewal, K., Schoenberger, S. P. & Green, D. R. Duration of CTL activation regulates IL-2 production required for autonomous clonal expansion. Eur. J. Immunol. 36, 1707–1717 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Mintern, J. D., Davey, G. M., Belz, G. T., Carbone, F. R. & Heath, W. R. Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells. J. Immunol. 168, 977–980 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Fuse, S. et al. Recall responses by helpless memory CD8+ T cells are restricted by the up-regulation of PD-1. J. Immunol. 182, 4244–4254 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Peperzak, V., Xiao, Y., Veraar, E. A. & Borst, J. CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production. J. Clin. Invest. 120, 168–178 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Janssen, E. M. et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Sacks, J. A. & Bevan, M. J. TRAIL deficiency does not rescue impaired CD8+ T cell memory generated in the absence of CD4+ T cell help. J. Immunol. 180, 4570–4576 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440, 890–895 (2006). This paper showed that T H cell-mediated licensing of DCs causes CCR5 ligand-mediated recruitment of naive CTLs for cross-priming.

    Article  CAS  PubMed  Google Scholar 

  67. Hugues, S. et al. Dynamic imaging of chemokine-dependent CD8+ T cell help for CD8+ T cell responses. Nature Immunol. 8, 921–930 (2007).

    Article  CAS  Google Scholar 

  68. Dorner, B. G. et al. Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity 31, 823–833 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Fujii, S., Shimizu, K., Hemmi, H. & Steinman, R. M. Innate Vα14+ natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol. Rev. 220, 183–198 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Semmling, V. et al. Alternative cross-priming through CCL17–CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nature Immunol. 11, 313–320 (2010). This paper showed that NKT cells can license DCs for cross-priming and recruit naive CTLs by CCR4 ligands.

    Article  CAS  Google Scholar 

  71. Wakim, L. M., Waithman, J., van Rooijen, N., Heath, W. R. & Carbone, F. R. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319, 198–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009). This report showed that cross-talk between DCs and T H cells in viral infections of mucosal tissue causes chemokine-mediated tissue recruitment of cross-primed CTLs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Marzo, A. L. et al. Tumor-specific CD4+ T cells have a major “post-licensing” role in CTL mediated anti-tumor immunity. J. Immunol. 165, 6047–6055 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Savinov, A. Y., Wong, F. S., Stonebraker, A. C. & Chervonsky, A. V. Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells. J. Exp. Med. 197, 643–656 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Galea, I. et al. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J. Exp. Med. 204, 2023–2030 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. von Oppen, N. et al. Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization. Hepatology 49, 1664–1672 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Dong, H. et al. B7-H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. Immunity 20, 327–336 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Reddehase, M. J. Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nature Rev. Immunol. 2, 831–844 (2002).

    Article  CAS  Google Scholar 

  79. Andrews, D. M., Andoniou, C. E., Granucci, F., Ricciardi-Castagnoli, P. & Degli-Esposti, M. A. Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Nature Immunol. 2, 1077–1084 (2001).

    Article  CAS  Google Scholar 

  80. Holtappels, R. et al. Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues. J. Exp. Med. 199, 131–136 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bickham, K. et al. Dendritic cells initiate immune control of Epstein-Barr virus transformation of B lymphocytes in vitro. J. Exp. Med. 198, 1653–1663 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bohm, V. et al. Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy. Med. Microbiol. Immunol. 197, 135–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Tewalt, E. F. et al. Viral sequestration of antigen subverts cross presentation to CD8+ T cells. PLoS Pathog. 5, e1000457 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Le Bon, A. et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nature Immunol. 4, 1009–1015 (2003). This paper revealed that type I IFN stimulates cross-priming.

    Article  CAS  Google Scholar 

  85. Lang, K. S. et al. Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J. Clin. Invest. 116, 2456–2463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215–229 (2005).

    Article  CAS  Google Scholar 

  87. Hosel, M. et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50, 1773–1782 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Sixt, M. et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19–29 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Datta, S. K. et al. Vaccination with irradiated Listeria induces protective T cell immunity. Immunity 25, 143–152 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Neuenhahn, M. et al. CD8α+ dendritic cells are required for efficient entry of Listeria monocytogenes into the spleen. Immunity 25, 619–630 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Kang, S. J., Liang, H. E., Reizis, B. & Locksley, R. M. Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells. Immunity 29, 819–833 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tseng, K. E., Chung, C. Y., H'Ng, W., S. & Wang, S. L. Early infection termination affects number of CD8+ memory T cells and protective capacities in Listeria monocytogenes-infected mice upon rechallenge. J. Immunol. 182, 4590–4600 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Schaible, U. E. et al. Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nature Med. 9, 1039–1046 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Winau, F. et al. Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24, 105–117 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Zehn, D. & Bevan, M. J. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity 25, 261–270 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. McDevitt, H. O. & Unanue, E. R. Autoimmune diabetes mellitus — much progress, but many challenges. Adv. Immunol. 100, 1–12 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. de Jersey, J. et al. β cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 104, 1295–1300 (2007). This paper showed that cross-priming is required for diabetes in the NOD mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hamilton-Williams, E. E. et al. Expression of diabetes-associated genes by dendritic cells and CD4 T cells drives the loss of tolerance in nonobese diabetic mice. J. Immunol. 183, 1533–1541 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. von Herrath, M. Diabetes: A virus-gene collaboration. Nature 459, 518–519 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Richer, M. J. & Horwitz, M. S. Coxsackievirus infection as an environmental factor in the etiology of type 1 diabetes. Autoimmun Rev. 8, 611–615 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Benoist, C. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nature Immunol. 2, 797–801 (2001).

    Article  CAS  Google Scholar 

  102. Pinkse, G. G. et al. Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes. Proc. Natl Acad. Sci. USA 102, 18425–18430 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nakayama, M. et al. Priming and effector dependence on insulin B: 9–23 peptide in NOD islet autoimmunity. J. Clin. Invest. 117, 1835–1843 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Luckashenak, N. et al. Constitutive crosspresentation of tissue antigens by dendritic cells controls CD8+ T cell tolerance in vivo. Immunity 28, 521–532 (2008). This report showed that non-transgenic self antigens can induce cross-tolerance.

    Article  CAS  PubMed  Google Scholar 

  105. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mohan, J. F. et al. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nature Immunol. 4, 350–354 (2010).

    Article  CAS  Google Scholar 

  107. Jahromi, M. M. & Eisenbarth, G. S. Cellular and molecular pathogenesis of type 1A diabetes. Cell. Mol. Life Sci. 64, 865–72 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Neilson, E. G., McCafferty, E., Mann, R., Michaud, L. & Clayman, M. Murine interstitial nephritis. III. The selection of phenotypic (Lyt and L3T4) and idiotypic (RE-Id) T cell preferences by genes in Igh-1 and H-XXXXX2K characterizes the cell-mediated potential for disease expression: susceptible mice provide a unique effector T cell repertoire in response to tubular antigen. J. Immunol. 134, 2375–2382 (1985).

    CAS  PubMed  Google Scholar 

  109. Gudjonsson, J. E., Johnston, A., Sigmundsdottir, H. & Valdimarsson, H. Immunopathogenic mechanisms in psoriasis. Clin. Exp. Immunol. 135, 1–8 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Goverman, J. Autoimmune T cell responses in the central nervous system. Nature Rev. Immunol. 9, 393–407 (2009).

    Article  CAS  Google Scholar 

  111. Perchellet, A., Brabb, T. & Goverman, J. M. Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein. Proc. Natl Acad. Sci. USA 105, 14040–14045 (2008). This paper implicated cross-tolerance in the control of encephalitogenic CTLs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Huseby, E. S. et al. A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis. J. Exp. Med. 194, 669–676 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Harkiolaki, M. et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity 30, 348–357 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Fiorillo, M. T. & Sorrentino, R. T-cell responses against viral and self-epitopes and HLA-B27 subtypes differentially associated with ankylosing spondylitis. Adv. Exp. Med. Biol. 649, 255–262 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Ichiki, Y. et al. T cell immunity in autoimmune hepatitis. Autoimmun. Rev. 4, 315–321 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Kammer, A. R. et al. Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition. J. Exp. Med. 190, 169–176 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gokmen, M. R., Lombardi, G. & Lechler, R. I. The importance of the indirect pathway of allorecognition in clinical transplantation. Curr. Opin. Immunol. 20, 568–574 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Boon, T., Cerottini, J. C., Van den Eynde, B., van der Bruggen, P. & Van Pel, A. Tumor antigens recognized by T lymphocytes. Annu. Rev. Immunol. 12, 337–365 (1994).

    Article  CAS  PubMed  Google Scholar 

  119. Boland, C. R. & Ricciardiello, L. How many mutations does it take to make a tumor? Proc. Natl Acad. Sci. USA 96, 14675–14677 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Marzo, A. L. et al. Tumor antigens are constitutively presented in the draining lymph nodes. J. Immunol. 162, 5838–5845 (1999).

    CAS  PubMed  Google Scholar 

  121. Cuenca, A. et al. Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res. 63, 9007–9015 (2003).

    CAS  PubMed  Google Scholar 

  122. Ney, J. T. et al. Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation. Hepatology 49, 471–481 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Gerner, M. Y., Casey, K. A. & Mescher, M. F. Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses. J. Immunol. 181, 155–164 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Stumbles, P. A. et al. Cutting edge: tumor-specific CTL are constitutively cross-armed in draining lymph nodes and transiently disseminate to mediate tumor regression following systemic CD40 activation. J. Immunol. 173, 5923–5928 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Nelson, D. J. et al. Tumor progression despite efficient tumor antigen cross-presentation and effective “arming” of tumor antigen-specific CTL. J. Immunol. 166, 5557–5566 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Lyman, M. A., Aung, S., Biggs, J. A. & Sherman, L. A. A spontaneously arising pancreatic tumor does not promote the differentiation of naive CD8+ T lymphocytes into effector CTL. J. Immunol. 172, 6558–6567 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Nguyen, L. T. et al. Tumor growth enhances cross-presentation leading to limited T cell activation without tolerance. J. Exp. Med. 195, 423–435 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nowak, A. K. et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J. Immunol. 170, 4905–4913 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Sauter, B. et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–434 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Schnurr, M. et al. Apoptotic pancreatic tumor cells are superior to cell lysates in promoting cross-priming of cytotoxic T cells and activate NK and γδ T cells. Cancer Res. 62, 2347–2352 (2002).

    CAS  PubMed  Google Scholar 

  131. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Lake, R. A. & Robinson, B. W. Immunotherapy and chemotherapy — a practical partnership. Nature Rev. Cancer 5, 397–405 (2005).

    Article  CAS  Google Scholar 

  133. Schnurr, M. et al. ISCOMATRIX adjuvant induces efficient cross-presentation of tumor antigen by dendritic cells via rapid cytosolic antigen delivery and processing via tripeptidyl peptidase II. J. Immunol. 182, 1253–1259 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Motta, I. et al. Cross-presentation by dendritic cells of tumor antigen expressed in apoptotic recombinant canarypox virus-infected dendritic cells. J. Immunol. 167, 1795–1802 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Bendz, H. et al. Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling. J. Biol. Chem. 282, 31688–31702 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Dhodapkar, K. M., Krasovsky, J., Williamson, B. & Dhodapkar, M. V. Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J. Exp. Med. 195, 125–133 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhang, H. et al. Comparing pooled peptides with intact protein for accessing cross-presentation pathways for protective CD8+ and CD4+ T cells. J. Biol. Chem. 284, 9184–9191 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Melief, C. J. & van der Burg, S. H. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nature Rev. Cancer 8, 351–360 (2008).

    Article  CAS  Google Scholar 

  140. Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361, 1838–1847 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Bretscher, P. & Cohn, M. A theory of self–nonself discrimination. Science 169, 1042–1049 (1970).

    Article  CAS  PubMed  Google Scholar 

  142. Bousso, P. & Albert, M. L. Signal 0 for guided priming of CTLs: NKT cells do it too. Nature Immunol. 11, 284–286 (2010).

    Article  CAS  Google Scholar 

  143. Robson, N. C., Hoves, S., Maraskovsky, E. & Schnurr, M. Presentation of tumour antigens by dendritic cells and challenges faced. Curr. Opin. Immunol. 22, 137–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Guermonprez, P. et al. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425, 397–402 (2003).

    Article  CAS  PubMed  Google Scholar 

  145. Houde, M. et al. Phagosomes are competent organelles for antigen cross-presentation. Nature 425, 402–406 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Touret, N. et al. Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell 123, 157–170 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. Savina, A. et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126, 205–218 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Di Pucchio, T. et al. Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I. Nature Immunol. 9, 551–557 (2008).

    Article  CAS  Google Scholar 

  149. Belizaire, R. & Unanue, E. R. Targeting proteins to distinct subcellular compartments reveals unique requirements for MHC class I and II presentation. Proc. Natl Acad. Sci. USA 106, 17463–17468 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zinkernagel, R. M. On cross-priming of MHC class I-specific CTL: rule or exception? Eur. J. Immunol. 32, 2385–2392 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Wolkers, M. C., Brouwenstijn, N., Bakker, A. H., Toebes, M. & Schumacher, T. N. Antigen bias in T cell cross-priming. Science 304, 1314–1317 (2004).

    Article  CAS  PubMed  Google Scholar 

  152. Burgdorf, S. et al. Steady-state cross-presentation of OVA is mannose receptor-dependent but inhibitable by collagen fragments. Proc. Natl Acad. Sci. USA 107, E48–E49 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Di Bonito, P. et al. Anti-tumor CD8+ T cell immunity elicited by HIV-1-based virus-like particles incorporating HPV-16 E7 protein. Virology 395, 45–55 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Kemball, C. C. et al. Coxsackievirus B3 inhibits antigen presentation in vivo, exerting a profound and selective effect on the MHC class I pathway. PLoS Pathog. 5, e1000618 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Racanelli, V., Behrens, S. E., Aliberti, J. & Rehermann, B. Dendritic cells transfected with cytopathic self-replicating RNA induce crosspriming of CD8+ T cells and antiviral immunity. Immunity 20, 47–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Ramirez, M. C. & Sigal, L. J. Macrophages and dendritic cells use the cytosolic pathway to rapidly cross-present antigen from live, vaccinia-infected cells. J. Immunol. 169, 6733–6742 (2002).

    Article  CAS  PubMed  Google Scholar 

  157. Lundie, R. J. et al. Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8α+ dendritic cells. Proc. Natl Acad. Sci. USA 105, 14509–14514 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Araujo, A. F. et al. CD8+-T-cell-dependent control of Trypanosoma cruzi infection in a highly susceptible mouse strain after immunization with recombinant proteins based on amastigote surface protein 2. Infect. Immun. 73, 6017–6025 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Steele, L. N., Balsara, Z. R. & Starnbach, M. N. Hematopoietic cells are required to initiate a Chlamydia trachomatis-specific CD8+ T cell response. J. Immunol. 173, 6327–6337 (2004).

    Article  CAS  PubMed  Google Scholar 

  160. Calzascia, T. et al. Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain. J. Immunol. 171, 2187–2191 (2003).

    Article  CAS  PubMed  Google Scholar 

  161. Brazillet, M. P., Batteux, F., Abehsira-Amar, O., Nicoletti, F. & Charreire, J. Induction of experimental autoimmune thyroiditis by heat-denatured porcine thyroglobulin: a Tc1-mediated disease. Eur. J. Immunol. 29, 1342–1352 (1999).

    Article  CAS  PubMed  Google Scholar 

  162. Sotomayor, E. M. et al. Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 98, 1070–1077 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Li, Y. et al. Efficient cross-presentation depends on autophagy in tumor cells. Cancer Res. 68, 6889–6895 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. Institutes of Molecular Medicine and Experimental Immunology, University Clinic of the Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Strasse 25, Bonn, 53105, Germany

    Christian Kurts & Percy A. Knolle

  2. School of Medicine and Pharmacology, Sir Charles Gairdner Hospital, University of Western Australia, Nedlands, 6009, Perth, Australia

    Bruce W. S. Robinson

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Glossary

Cross-presentation

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

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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