Surface CD152 (CTLA-4) expression and signaling dictates longevity of CD28null T cells.
CD28(null) T cells are a highly enriched subset of proinflammatory T cells in patients with autoimmune diseases that are oligoclonal and autoreactive. In this study, we analyzed the role of CD152 signaling on the longevity of human CD28(null) T cells. Using a sensitive staining method for CD152, we show that human CD4(+)CD28(null) and CD8(+)CD28(null) T cells rapidly express surface CD152. Serological inactivation of CD152 using specific Fab or blockade of CD152 ligands using CTLA-4Ig in CD4(+)CD28(null) and CD8(+)CD28(null) T cells enhances apoptosis in a Fas/FasL-dependent manner. CD152 cross-linking on activated CD28(null) cells prevents activation-induced cell death as a result of reduced caspase activity. Apoptosis protection conferred by CD152 is mediated by phosphatidylinositol 3'-kinase-dependent activation of the kinase Akt, resulting in enhanced phosphorylation and thereby inhibition of the proapoptotic molecule Bad. We show that signals triggered by CD152 act directly on activated CD28(null) T lymphocytes and, due to its exclusive expression as a receptor for CD80/CD86 on CD28(null) T cells, prevention of CD152-mediated signaling is likely a target mechanism taking place during therapy with CTLA-4Ig. Our data imply strongly that antagonistic approaches using CD152 signals for chronic immune responses might be beneficial.
Hoff
Holger
H
Department of Pediatrics, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany.
Knieke
Karin
K
Cabail
Zulema
Z
Hirseland
Heike
H
Vratsanos
George
G
Burmester
Gerd-Rüdiger
GR
Jorch
Gerhard
G
Nadler
Steven G
SG
Bröker
Barbara
B
Hebel
Katrin
K
Brunner-Weinzierl
Monika C
MC
D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008215:Lymphocytes, Null / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D008565:Membrane Proteins