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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4285-4292. Prepublished online as a Blood First Edition Paper on August 27, 2007; DOI 10.1182/blood-2007-05-088286. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-05-088286v1 110/13/4285    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mateo, V. Articles by Rieux-Laucat, F. Search for Related Content PubMed PubMed Citation Articles by Mateo, V. Articles by Rieux-Laucat, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 3, 2007 Accepted August 6, 2007 Perforin-dependent apoptosis functionally compensates Fas-deficiency in Activation-induced cell-death of human T-lymphocytes Veronique Mateo, Michael Menager, Genevieve de Saint-Basile, Marie-Claude Stolzenberg, Bertrand Roquelaure, Nicolas Andre, Benoit Florkin, Francoise le Deist, Capucine Picard, Alain Fischer, and Frederic Rieux-Laucat* INSERM, U768; Universite Rene Descartes-Paris 5, Hopital Necker-Enfants Malades, Paris, France Centre d'etude des deficites Immunitaires, Assistance Publique - Hopitaux de Paris, Hopital Necker-Enfants Malades, Paris, France Multidisciplinary Department of Pediatrics, Children Hospital of La Timone, Marseille, France Departement de pediatrie, Centre Hospitalier Universitaire de Liege, Liege, Belgium Departement de Microbiologie et d'Immunologie, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada Unite d'Immunologie et Hematologie Pediatrique, Assistance Publique - Hopitaux de Paris, Hopital Necker-Enfants Malades, Paris, France * Corresponding author; email: rieux{at}necker.fr. Activation-Induced Cell Death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)-dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering Autoimmune Lymphoproliferative Syndrome (ALPS), characterized by lymphoproliferation and autoimmunity. In this study, we examined AICD in Fas deficient T-cells from ALPS patients. We showed that primary activated Fas-deficient T-cells die by apoptosis after repeated TCR stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway as it is inhibited by compounds that inactivated the cytotoxic-granules content. Cytotoxic granules-mediated AICD was also detected in normal T-lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients that exhibited defective granules-dependent cytotoxicity. Supporting an in-vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell-death in ALPS may compensate for Fas-deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T-lymphocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Bristeau-Leprince, V. Mateo, A. Lim, A. Magerus-Chatinet, E. Solary, A. Fischer, F. Rieux-Laucat, and M.-L. Gougeon Human TCR {alpha}/{beta}+ CD4-CD8- Double-Negative T Cells in Patients with Autoimmune Lymphoproliferative Syndrome Express Restricted V{beta} TCR Diversity and Are Clonally Related to CD8+ T Cells J. Immunol., July 1, 2008; 181(1): 440 - 448. [Abstract] [Full Text] [PDF]

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