Molecular basis of T cell inactivation by CTLA-4

Science. 1998 Dec 18;282(5397):2263-6. doi: 10.1126/science.282.5397.2263.

Abstract

CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex zeta chain in primary T cells. The association of TCRzeta with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56(lck)-induced tyrosine phosphorylation. Coexpression of the CTLA-4-associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRzeta bound to CTLA-4 and abolished the p56(lck)-inducible TCRzeta-CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRzeta and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / metabolism*
  • CTLA-4 Antigen
  • Cell Line
  • Cells, Cultured
  • Humans
  • Immunoconjugates*
  • Intracellular Signaling Peptides and Proteins
  • Lymphocyte Activation*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Models, Immunological
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism
  • Receptors, Antigen, T-Cell / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Signal Transduction*
  • T-Lymphocytes / immunology*
  • Transfection
  • src Homology Domains

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • antigen T cell receptor, zeta chain
  • Phosphotyrosine
  • Abatacept
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • PTPN11 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse
  • SH2 Domain-Containing Protein Tyrosine Phosphatases