CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function.
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.
Deutsches Rheuma-Forschungszentrum, Schumannstrasse 21/22, 10117 Berlin, Germany.
Pushpa
P
Pandiyan
Dagmar
D
Gärtner
Osman
O
Soezeri
Andreas
A
Radbruch
Klaus
K
Schulze-Osthoff
Monika C
MC
Brunner-Weinzierl
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology* / Q000502:physiology; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000502:physiology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D053222:Fas Ligand Protein; D005455:Fluorescent Antibody Technique / Q000379:methods; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D019254:Genes, bcl-2 / Q000502:physiology; D005838:Genotype; D019044:Image Cytometry; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008863:Microspheres; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008562:Membrane Glycoproteins; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases