Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation

J Immunol. 2004 Dec 15;173(12):7135-9. doi: 10.4049/jimmunol.173.12.7135.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept
  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / physiology*
  • B7-1 Antigen / metabolism
  • B7-1 Antigen / pharmacology
  • CD28 Antigens / genetics
  • CD28 Antigens / physiology*
  • CTLA-4 Antigen
  • Cell Proliferation
  • Cells, Cultured
  • Drug Synergism
  • Female
  • Growth Inhibitors / pharmacology
  • Humans
  • Immunoconjugates / pharmacology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-cbl
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Ubiquitin-Protein Ligases / biosynthesis
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Adjuvants, Immunologic
  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cblb protein, mouse
  • Ctla4 protein, mouse
  • Growth Inhibitors
  • Immunoconjugates
  • Abatacept
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases