title: Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation.
abstract: Cbl-b negatively regulates CD28-dependent T cell activation. In this report, we tested the hypothesis that CD28 and CTLA-4 have opposite roles in tuning T cell activation threshold by controlling the levels of Cbl-b protein expression. We demonstrate that CD28 costimulation potentiates TCR-induced Cbl-b degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. In support of this finding, Cbl-b expression in CTLA-4 knockout (KO) T cells is significantly reduced, and treating CTLA-4KO mice with human CTLA-4Ig to block CD28-B7 interaction restores Cbl-b expression on T cells. Furthermore, CD28 and CTLA-4 costimulatory effects are compromised in Cbl-bKO T cells. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation.
authors.affiliation: Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Li
authors.forename: István
authors.initials: I
authors.lastname: Gál
authors.forename: Csaba
authors.initials: C
authors.lastname: Vermes
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
authors.forename: Anita S F
authors.initials: AS
authors.lastname: Chong
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.forename: Vyacheslava
authors.initials: V
authors.lastname: Adarichev
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xu
authors.forename: Tamas
authors.initials: T
authors.lastname: Koreny
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Alison
authors.initials: A
authors.lastname: Finnegan
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000069594:Abatacept; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000378:metabolism / Q000494:pharmacology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050721:Proto-Oncogene Proteins c-cbl; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C118387:Cblb protein, mouse; C556707:Ctla4 protein, mouse; D006131:Growth Inhibitors; D018796:Immunoconjugates; D000069594:Abatacept; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases