The Journal of Immunology, Vol 156, Issue 9 3184-3190, Copyright © 1996 by American Association of Immunologists

ARTICLES

CD2-induced apoptosis in activated human peripheral T cells: a Fas- independent pathway that requires early protein tyrosine phosphorylation

B Mollereau, M Deckert, O Deas, F Rieux-Laucat, F Hirsch, A Bernard, A Fischer, DH Lynch, B Charpentier, F Le Deist and A Senik
Equipe d'Immunologie Cellulaire et de Transplantation, Villejuif, France.

Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic "death" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction.

This article has been cited by other articles:

				C. Goda, T. Kanaji, S. Kanaji, G. Tanaka, K. Arima, S. Ohno, and K. Izuhara Involvement of IL-32 in activation-induced cell death in T cells Int. Immunol., February 1, 2006; 18(2): 233 - 240. [Abstract] [Full Text] [PDF]

				X.-M. Chen, G. J. Gores, C. V. Paya, and N. F. LaRusso Cryptosporidium parvum induces apoptosis in biliary epithelia by a Fas/Fas ligand-dependent mechanism Am J Physiol Gastrointest Liver Physiol, September 1, 1999; 277(3): G599 - G608. [Abstract] [Full Text] [PDF]

				N. Sawai, K. Koike, S. Ito, Y. Kurokawa, H. H. Mwamtemi, T. Kinoshita, K. Sakashita, T. Higuchi, K. Takeuchi, M. Shiohara, et al. Apoptosis of Erythroid Precursors under Stimulation with Thrombopoietin: Contribution to Megakaryocytic Lineage Choice Stem Cells, January 1, 1999; 17(1): 45 - 54. [Abstract] [Full Text]

				P. Scheipers and H. Reiser Fas-independent death of activated CD4+ T lymphocytes induced by CTLA-4 crosslinking PNAS, August 18, 1998; 95(17): 10083 - 10088. [Abstract] [Full Text] [PDF]

				D. Wesch, S. Marx, and D. Kabelitz Monocyte-Dependent Death of Freshly Isolated T Lymphocytes: Induction by Phorbolester and Mitogens and Differential Effects of Catalase J. Immunol., August 1, 1998; 161(3): 1248 - 1256. [Abstract] [Full Text] [PDF]

				H.-U. Simon, S. Yousefi, B. Dibbert, H. Hebestreit, M. Weber, D. R. Branch, K. Blaser, F. Levi-Schaffer, and G. P. Anderson Role for Tyrosine Phosphorylation and Lyn Tyrosine Kinase in Fas Receptor-Mediated Apoptosis in Eosinophils Blood, July 15, 1998; 92(2): 547 - 557. [Abstract] [Full Text] [PDF]

				S. Fournel, E. Robinet, N. Bonnefoy-Berard, O. Assossou, M. Flacher, H. Waldmann, G. Bismuth, and J.-P. Revillard A Noncomitogenic CD2R Monoclonal Antibody Induces Apoptosis of Activated T Cells by a CD95/CD95-L-Dependent Pathway J. Immunol., May 1, 1998; 160(9): 4313 - 4321. [Abstract] [Full Text] [PDF]

				L. Genestier, S. Fournel, M. Flacher, O. Assossou, J.-P. Revillard, and N. Bonnefoy-Berard Induction of Fas (Apo-1, CD95)-Mediated Apoptosis of Activated Lymphocytes by Polyclonal Antithymocyte Globulins Blood, April 1, 1998; 91(7): 2360 - 2368. [Abstract] [Full Text] [PDF]

				L. Genestier, A.-F. Prigent, R. Paillot, L. Quemeneur, I. Durand, J. Banchereau, J. P. Revillard, and N. Bonnefoy-Berard Caspase-dependent Ceramide Production in Fas- and HLA Class I-mediated Peripheral T Cell Apoptosis J. Biol. Chem., February 27, 1998; 273(9): 5060 - 5066. [Abstract] [Full Text] [PDF]

				L. Genestier, R. Paillot, N. Bonnefoy-Berard, G. Meffre, M. Flacher, D. Fevre, Y. J. Liu, P. Le Bouteiller, H. Waldmann, V. H. Engelhard, et al. Fas-Independent Apoptosis of Activated T Cells Induced by Antibodies to the HLA Class I alpha 1 Domain Blood, November 1, 1997; 90(9): 3629 - 3639. [Abstract] [Full Text] [PDF]