CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells.
While interactions between CD28 and members of the B7 family costimulate and enhance T cell responses, recent evidence indicates that the CD28 homologue CTLA-4 plays a downregulatory role. The mechanism by which this occurs is not clear, but it has been suggested that CTLA-4 terminates ongoing responses of activated T cells, perhaps by induction of apoptosis. Here we demonstrate that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti-CD3 and anti-CD28. This inhibition is not a result of enhanced cell death. Rather it appears to result from restriction of transition from the G1 to the S phase of the cell cycle. Our observation that upregulation of both the IL-2R alpha chain and the CD69 activation antigen are inhibited by CTLA-4 engagement supplies further evidence that CTLA-4 restricts the progression of T cells to an activated state. Together this data demonstrates that CTLA-4 can regulate T cell activation in the absence of induction of apoptotic cell death.
Krummel
M F
MF
Department of Molecular and Cell Biology, University of California, Berkeley 94720, USA.
Allison
J P
JP
D000069594:Abatacept; D000818:Animals; D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000276:immunology*; D002478:Cells, Cultured; D018914:Cells, Immobilized; D003432:Cross-Linking Reagents; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis*; D007700:Kinetics; D007840:Latex; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D013997:Time Factors
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; D003432:Cross-Linking Reagents; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D007840:Latex; D000069594:Abatacept