CTLA-4 binding to the lipid kinase phosphatidylinositol 3-kinase in T cells

J Exp Med. 1995 Jan 1;181(1):351-5. doi: 10.1084/jem.181.1.351.

Abstract

CTLA-4 is a T cell antigen that is structurally related to CD28 and serves as a high affinity ligand for the B cell antigen B7-1/2. Unlike CD28, the function of CTLA-4 is unclear, although reports have implicated the antigen in the costimulation of T cells. Recently, phosphatidylinositol 3-kinase (PI 3-kinase) has been implicated in the costimulatory function of CD28 by virtue of its ability to bind to a pYMNM motif within the cytoplasmic tail of the antigen. In this study, we show that CTLA-4 can also associate with PI 3-kinase as detected by lipid kinase analysis and immunoblotting with anti-p85 antiserum. High pressure liquid chromatographic separation of deacylated lipids showed the presence of a peak corresponding to PI-3-P. Anti-CTLA-4 ligation of the receptor induced a significant increase in the levels of precipitable PI 3-kinase activity. Peptide binding studies revealed that the NH2- and COOH-terminal SH2 domains of p85 bind the CTLA-4 cytoplasmic pYVKM motif with an affinity (ID50: 0.6 and 0.04 microM), that is similar to CD28. CTLA-4 binding to PI 3-kinase provides further evidence that CTLA-4 is not an inert counterreceptor, but rather is coupled to an intracellular signaling molecule with the capacity to regulate cell growth.

Publication types

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

MeSH terms

  • Abatacept
  • Amino Acid Sequence
  • Antigens, CD
  • Antigens, Differentiation / metabolism*
  • CTLA-4 Antigen
  • Humans
  • Immunoconjugates*
  • In Vitro Techniques
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases
  • Phosphopeptides / chemistry
  • Phosphopeptides / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Binding
  • Signal Transduction
  • T-Lymphocytes / enzymology*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immunoconjugates
  • Phosphopeptides
  • Abatacept
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)