Antagonistic roles for CTLA-4 and the mammalian target of rapamycin in the regulation of clonal anergy: enhanced cell cycle progression promotes recall antigen responsiveness.
CD4(+) T cells that undergo multiple rounds of cell division during primary Ag challenge in vivo produce IL-2 on secondary Ag rechallenge, whereas cells that fail to progress through the cell cycle are anergic to restimulation. Anti-CTLA-4 mAb treatment during primary Ag exposure increases cell cycle progression and enhances recall Ag responsiveness; however, simultaneous treatment with rapamycin, an inhibitor of the mammalian target of rapamycin and potent antiproliferative agent, prevents both effects. The data suggest that cell cycle progression plays a primary role in the regulation of recall Ag responsiveness in CD4(+) T cells in vivo. CTLA-4 molecules promote clonal anergy development only indirectly by limiting cell cycle progression during the primary response.
Vanasek
T L
TL
Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Khoruts
A
A
Zell
T
T
Mueller
D L
DL
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects; D019672:Genes, T-Cell Receptor; D018796:Immunoconjugates; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D000069594:Abatacept; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus