The Journal of Experimental Medicine
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Published online 8 March 2004 doi:10.1084/jem.20031058
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 6, 831-842
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CD152 (CTLA-4) Determines the Unequal Resistance of Th1 and Th2 Cells against Activation-induced Cell Death by a Mechanism Requiring PI3 Kinase Function

Pushpa Pandiyan1, Dagmar Gärtner1, Osman Soezeri1, Andreas Radbruch1, Klaus Schulze-Osthoff2, and Monika C. Brunner-Weinzierl1,3

1 Deutsches Rheuma-Forschungszentrum Berlin, 2 Institut für Molekulare Medizin, Universität Düsseldorf, and 3 Medizinische Kliniken der Humboldt-Universität zu Berlin, Charité, 10117 Berlin, Germany

Address correspondence to Monika C. Brunner-Weinzierl, Deutsches Rheuma-Forschungszentrum, Schumannstrasse 21/22, 10117 Berlin, Germany. Phone: 49-30-28460-721; Fax: 49-30-28460-603; email: brunner{at}drfz.de

Survival of antigen-experienced T cells is essential for the generation of adaptive immune responses. Here, we show that the genetic and antibody-mediated inactivation of CD152 (cytotoxic T lymphocyte antigen 4) in T helper (Th) effector cells reduced the frequency of nonapoptotic cells in a completely Fas/Fas ligand (FasL)–dependent manner. CD152 cross-linking together with stimulation of CD3 and CD28 on activated Th2 cells prevented activation-induced cell death (AICD) as a result of reduced Fas and FasL expression. Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1. We show that signals induced by CD152 act directly on activated T lymphocytes and, due to its differential surface expression on activated Th1 and Th2 cells, induce resistance to AICD mainly in Th2 cells.

Key Words: costimulation • apoptosis • survival • signal transduction • FasL

Abbreviations used in this paper: AICD, activation-induced cell death; CFSE, 5,6-carboxyfluorescein diacetate succinimidyl ester; dB-cAMP, dibutyryl cAMP; FasL, Fas ligand; tg, transgenic; PI, propidium iodide; PI3 K, phosphatidylinositol 3 kinase; TUNEL, TdT-mediated dUTP nick-end labeling.


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