Tuning Cross-Presentation of Apoptotic T Cells in Immunopathology

  • Vincenzo BarnabaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 785)


Cross-presentation of several long-lived antigens associated with apoptotic T cells requires caspase-dependent cleavage to efficiently deliver antigenic fragments to the processing machinery of antigen-presenting cells. The resulting emergence of a large population of autoreactive CD8+ T effector cells specific for apoptotic T cell-associated self-epitopes plays a key role in improving immunopathology in several infections and autoimmune diseases. Importantly, they endow mixed polyfunctional type-1, type-2, and type-17 responses and correlate with the chronic progression of various pathological conditions. This evolution is related to the selection of autoreactive CD8+ T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients undergoing disease resolution. The development of mixed responses with divergent differentiation requirements is consistent with distinct sites or kinetics of CD8+ T cell priming in vivo. Therefore, we propose a strict link among cross-presentation of apoptotic T cells, the generation of high frequencies of mixed autoreactive CD8+ T cells producing a broad array of cytokines (IFN-γ, IL-17, IL-4, IL-2, etc.), and the progression towards chronic inflammatory diseases.


Cross-presentation Apoptotic T cells Apoptotic epitope-specific CD8+ T cells 



This work was supported by the following: European Union grants (IMECS n. 201169, FP7-Health-2007-A and SPHYNX n. 261365, FP7-Health-2010); Ministero della Sanità (Ricerca finalizzata [RFPS-2006-3-337923 and RFPS-2007-1-636647]; Istituto Superiore di Sanità [Progetto AIDS-2006 and -2008]); Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (Programmi di ricerca di interesse nazionale [PRIN]-2008/10 n. 7245/1; Fondo per gli investimenti di ricerca di base [FIRB]-2011/13 n. RBAP10TPXK); Fondazione Cariplo (progetti n. 13535 and 3603 2010/12); and Associazione Italiana per la Ricerca sul Cancro (AIRC) (progetto “Investigator Grant” [IG]-2010/13 n. 10756).


  1. 1.
    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: 1283–1288.PubMedCrossRefGoogle Scholar
  2. 2.
    Heath WR, Carbone FR (2001) Cross-presentation, dendritic cells, tolerance and immunity. Ann. Rev. Immunol.19: 47–64.CrossRefGoogle Scholar
  3. 3.
    Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106: 255–258.PubMedCrossRefGoogle Scholar
  4. 4.
    Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annual review of immunology 21: 685–711.PubMedCrossRefGoogle Scholar
  5. 5.
    Matzinger P (2002) The danger model: a renewed sense of self. Science 296: 301–305.PubMedCrossRefGoogle Scholar
  6. 6.
    Medzhitov, R. (2010). Inflammation 2010: new adventures of an old flame. Cell 140, 771–776.PubMedCrossRefGoogle Scholar
  7. 7.
    Yamazaki, S., Inaba, K., Tarbell, K.V. and Steinman, R.M. (2006). Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol. Rev. 212, 314–329.PubMedCrossRefGoogle Scholar
  8. 8.
    Sakaguchi, S., Miyara, M., Costantino, C.M. and Hafler, D.A. (2010). FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500.PubMedCrossRefGoogle Scholar
  9. 9.
    Green DR, Ferguson T, Zitvogel L, Kroemer G (2009) Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9: 353–363.PubMedCrossRefGoogle Scholar
  10. 10.
    Ravichandran KS (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J. Exp. Med. 207: 1807–1817.PubMedCrossRefGoogle Scholar
  11. 11.
    Nuti S, Rosa D, Valiante NM, Saletti G, et al. (1998) Dynamics of intra-hepatic lymphocytes in chronic hepatitis C: enrichment for Valpha24+ T cells and rapid elimination of effector cells by apoptosis. Eur. J. Immunol. 28: 3448–3455.PubMedCrossRefGoogle Scholar
  12. 12.
    Propato, A., Cutrona, G., Francavilla, V., Ulivi, M., et al. (2001). Apoptotic cells overexpress vinculin and induce vinculin-specific cytotoxic T-cell cross-priming. Nat Med 7, 807–813.PubMedCrossRefGoogle Scholar
  13. 13.
    Winau, F., Weber, S., Sad, S., de Diego, J., Hoops, S.L., Breiden, B., Sandhoff, K., Brinkmann, V., Kaufmann, S.H. and Schaible, U.E. (2006). Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24, 105–117.PubMedCrossRefGoogle Scholar
  14. 14.
    Ferguson, T.A., Green, D.R. and Griffith, T.S. (2002). Cell death and immune privilege. Int Rev Immunol 21, 153–172.PubMedCrossRefGoogle Scholar
  15. 15.
    Kurts, C., Heath, W.R., Kosaka, H., Miller, J.F. and Carbone, F.R. (1998). The peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1). J. Exp. Med. 188, 415–420.PubMedCrossRefGoogle Scholar
  16. 16.
    Chen, W., Frank, M.E., Jin, W. and Wahl, S.M. (2001). TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14, 715–725.PubMedCrossRefGoogle Scholar
  17. 17.
    Gao, Y., Herndon, J.M., Zhang, H., Griffith, T.S. and Ferguson, T.A. (1998). Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis. J. Exp. Med. 188, 887–896.PubMedCrossRefGoogle Scholar
  18. 18.
    Serhan, C.N. and Savill, J. (2005). Resolution of inflammation: the beginning programs the end. Nat Immunol 6, 1191–1197.PubMedCrossRefGoogle Scholar
  19. 19.
    Kazama, H., Ricci, J.E., Herndon, J.M., Hoppe, G., Green, D.R. and Ferguson, T.A. (2008). Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Albert, M.L. (2004). Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol 4, 223–231.PubMedCrossRefGoogle Scholar
  21. 21.
    Inaba, K., Turley, S., Yamaide, F., Iyoda, et al. (1998). Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J. Exp. Med. 188, 2163–2173.Google Scholar
  22. 22.
    Rawson PM, Molette C, Videtta M, Altieri L, Franceschini D, et al. (2007) Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection. Nat. Med. 13: 1431–1439.PubMedCrossRefGoogle Scholar
  23. 23.
    Tesniere, A., Apetoh, L., Ghiringhelli, F., Joza, et al. (2008). Immunogenic cancer cell death: a key-lock paradigm. Curr Opin Immunol 20, 504–511.Google Scholar
  24. 24.
    De Vita, L., Accapezzato, D., Mangino, G., Morrone, S., et al. (1998). Defective Th1 and Th2 cytokine synthesis in the T-T cell presentation model for lack of CD40/CD40 ligand interaction. Eur. J. Immunol. 28, 3552–3563.PubMedCrossRefGoogle Scholar
  25. 25.
    Gurung P, Kucaba TA, Ferguson TA, Griffith TS (2009) Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells. J. Immunol. 183: 6114–6123.PubMedCrossRefGoogle Scholar
  26. 26.
    Yewdell, JW, Anton LC, and Bennink JR (1996). Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules? J. Immunol. 157, 1823–1826.PubMedGoogle Scholar
  27. 27.
    Joubert P-E, and Albert ML (2012). Antigen cross-priming of cell-associated proteins is enhanced by macroautophagy within antigen donor cells. Front Immunol. Doi: 10.3399/fimmu. 2012.00061.Google Scholar
  28. 28.
    Accapezzato D, Visco V, Francavilla V, Molette C, et al. (2005) Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J. Exp. Med. 202, 817–828.PubMedCrossRefGoogle Scholar
  29. 29.
    Pang B, Neijssen J, Qiao X, Janssen L, Janssen H, et al. (2009) Direct antigen presentation and gap junction mediated cross-presentation during apoptosis. J. Immunol. 183: 1083–1090.PubMedCrossRefGoogle Scholar
  30. 30.
    Lopez D, Garcia-Calvo M, Smith GL, Del Val M (2010) Caspases in virus-infected cells contribute to recognition by CD8+ T lymphocytes. J. Immunol. 184: 5193–5199.PubMedCrossRefGoogle Scholar
  31. 31.
    Rock KL, Farfan-Arribas DJ, Shen L (2010) Proteases in MHC class I presentation and cross-presentation. J. Immunol. 184: 9–15.PubMedCrossRefGoogle Scholar
  32. 32.
    Franceschini D, Del Porto P, Piconese S, Trella E et al. (2012). Polyfunctional type-1, -2, and -17 CD8+ T Cell responses to apoptotic self-antigens progress with the chronic evolution of hepatitis C virus infection. Plos Pathogens. 2012; 8(6):e1002759. Doi: 10.1371/journal.ppat.1002759. Epub 2012 Jun 21.Google Scholar
  33. 33.
    Wu HJ, Ivanov, II, Darce J, Hattori K, Shima T, et al. (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32: 815–827.PubMedCrossRefGoogle Scholar
  34. 34.
    Savage PA, Boniface JJ, Davis MM (1999) A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 10: 485–492.PubMedCrossRefGoogle Scholar
  35. 35.
    Zehn D, Lee SY, Bevan MJ (2009) Complete but curtailed T-cell response to very low-affinity antigen. Nature 458: 211–214.PubMedCrossRefGoogle Scholar
  36. 36.
    van Heijst JW, Gerlach C, Swart E, Sie D, Nunes-Alves C, et al. (2009) Recruitment of antigen-specific CD8+ T cells in response to infection is markedly efficient. Science 325: 1265–1269.PubMedCrossRefGoogle Scholar
  37. 37.
    Barnaba V, Paroli M, Piconese S (2012) The ambiguity in immunology. Front. Immunol. 2012; 3:18. doi: 10.3389/fimmu.2012.00018. Epub 2012 Feb 22.Google Scholar
  38. 38.
    Barnaba V. Hepatitis C virus infection: a “liaison a trois” amongst the virus, the host, and chronic low-level inflammation for human survival. J Hepatol 53(4):752–61, 2010.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Policlinico Umberto I, Dipartimento di Medicina Interna e Specialità MedicheSapienza Università di RomaRomeItaly
  2. 2.Istituto Pasteur-Fondazione Cenci BolognettiRomeItaly
  3. 3.Fondazione Andrea CesalpinoRomeItaly

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