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Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection

Nature Medicine volume 13, pages 1431–1439 (2007)Cite this article

Abstract

We found that the proteome of apoptotic T cells includes prominent fragments of cellular proteins generated by caspases and that a high proportion of distinct T cell epitopes in these fragments is recognized by CD8+ T cells during HIV infection. The frequencies of effector CD8+ T cells that are specific for apoptosis-dependent epitopes correlate with the frequency of circulating apoptotic CD4+ T cells in HIV-1–infected individuals. We propose that these self-reactive effector CD8+ T cells may contribute to the systemic immune activation during chronic HIV infection. The caspase-dependent cleavage of proteins associated with apoptotic cells has a key role in the induction of self-reactive CD8+ T cell responses, as the caspase-cleaved fragments are efficiently targeted to the processing machinery and are cross-presented by dendritic cells. These findings demonstrate a previously undescribed role for caspases in immunopathology.

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Figure 1: Proteomic analysis of apoptotic or live T cell clones and effector CD8+ T cell repertoire in people with HIV.
Figure 2: Detection of apoptotic antigen–specific CD8+ T cells by pentamers.
Figure 3: Correlation between the self- or HIV-specific efCD8+ T cell repertoire and apoptosis in vivo in individuals with HIV.
Figure 4: Caspase-dependent cross-presentation of apoptotic antigens.
Figure 5: Cross-presentation of soluble vimentin purified from apoptotic cells.

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Acknowledgements

This work was supported by the European Union; the Fondo per gli Investimenti della Ricerca di Base and Programmi di Ricerca scientifica di rilevante Interesse Nazionale, Ministero dell'Istruzione, dell'Università e della Ricerca projects; the Ministero della Sanità-Istituto Superiore di Sanità (Progetti AIDS); the Ministero della Sanità-Ricerca finalizzata HCV; the Associazione Italiana per la Ricerca sul Cancro; the Fondazione Italiana Sclerosi Multipla; and Contributo Regione Lazio per la realizzazione di opere strutturali ed iniziative sociali, culturali e sportive di carattere locale 2006. Recombinant IL-4, CD40L-transfected J558L cells, and rabbit polyclonal antibody to αvβ5 antibody were donated by A. Lanzavecchia (Institute for Research in Biomedicine, Bellinzona, Switzerland), P. Lane (University of Birmingham Medical School, Birmingham, UK) and G. Santoni (Università di Camerino, Italy), respectively.

Author information

Author notes

  1. Pisana Moroni Rawson & Caroline Molette

    Present address: Present addresses: Centre of Biodiscovery, Victoria University of Wellington, Kelburn Parade, Wellington, New Zealand (P.M.R.); Laboratoire Zootechnie et Qualite des Produits Animaux, École Nationale Superieure Agronomique de Toulouse, Avenue de l'Agrobiopole, BP 32607, 31326 Castanet Tolosan CEDEX, France (C.M.).,

  2. Pisana Moroni Rawson and Caroline Molette: These authors contributed equally to this work.

Authors and Affiliations

  1. Fondazione Andrea Cesalpino — Dipartimento di Medicina Interna, Sapienza Università di Roma, 00161, Rome, Italy

    Pisana Moroni Rawson, Caroline Molette, Melissa Videtta, Laura Altieri, Debora Franceschini, Tiziana Donato, Luigi Finocchi, Antonella Propato, Marino Paroli, Francesca Meloni & Vincenzo Barnaba

  2. Dipartimento di Malattie Infettive e Tropicali, Sapienza Università di Roma, 00161, Rome, Italy

    Claudio M Mastroianni & Gabriella d'Ettorre

  3. La Jolla Institute for Allergy and Immunology, San Diego, 92121, California, USA

    John Sidney & Alessandro Sette

  4. Istituto Pasteur-Cenci Bolognetti, Sapienza Università di Roma, 00161, Rome, Italy

    Vincenzo Barnaba

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Contributions

P.M.R., C.M., M.V., T.D. and L.F. conducted proteomic and molecular analyses; L.A., D.F., A.P. and F.M. performed immunology experiments (cross-presentation, flow cytometry analyses and T cell cloning); M.P., C.M.M. and G.d'E. procured samples and recruited subjects; J.S. and A.S. synthesized peptides; V.B. conceived the study and wrote the manuscript.

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Correspondence to Vincenzo Barnaba.

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Rawson, P., Molette, C., Videtta, M. et al. Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection. Nat Med 13, 1431–1439 (2007). https://doi.org/10.1038/nm1679

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