Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation.
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.
Li
Dongdong
D
Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA.
Gál
István
I
Vermes
Csaba
C
Alegre
Maria-Luisa
ML
Chong
Anita S F
AS
Chen
Lieping
L
Shao
Qing
Q
Adarichev
Vyacheslava
V
Xu
Xuemei
X
Koreny
Tamas
T
Mikecz
Katalin
K
Finnegan
Alison
A
Glant
Tibor T
TT
Zhang
Jian
J
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*
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