CTLA-4 regulates induction of anergy in vivo.
The requirement for CTLA-4 during the induction of peripheral T cell tolerance in vivo was investigated using naive TCR transgenic T cells lacking CTLA-4. CTLA-4(-/-) T cells are resistant to tolerance induction, as demonstrated by their proliferative responses, IL-2 production, and progression into the cell cycle. Following exposure to a tolerogenic stimulus in vivo and restimulation in vitro, wild-type T cells are blocked at the late G1 to S restriction point of the cell cycle. In contrast, CTLA-4(-/-) T cells enter into the S phase of the cell cycle, as shown by downregulation of p27(kip1), elevated cdk2 kinase activity, and Rb hyperphosphorylation. Thus, CTLA-4 has an essential role in determining the outcome of T cell encounter with a tolerogenic stimulus.
Greenwald
R J
RJ
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Boussiotis
V A
VA
Lorsbach
R B
RB
Abbas
A K
AK
Sharpe
A H
AH
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D017635:Clonal Anergy / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D007108:Immune Tolerance; D018796:Immunoconjugates; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D018796:Immunoconjugates; D007376:Interleukin-2; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D000069594:Abatacept