Negative regulation of T cell receptor-lipid raft interaction by cytotoxic T lymphocyte-associated antigen 4

J Exp Med. 2003 Jan 6;197(1):129-35. doi: 10.1084/jem.20021646.

Abstract

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an essential negative regulator of T cell activation. Recent evidence suggests that CTLA-4 association with the immunological synapse during contact with antigen-presenting cells is important for its inhibitory function. In the present study, we observed a direct interaction of CTLA-4 with the phosphorylated form of T cell receptor (TCR)zeta within the glycolipid-enriched microdomains associated with the T cell signaling complex. In this setting, CTLA-4 regulated the accumulation/retention of TCRzeta in the signaling complex, as the lipid raft fractions from CTLA-4KO T cells contained significantly higher amounts of the TCR components when compared with wild-type littermates. In contrast, coligation of CTLA-4 with the TCR during T cell activation selectively decreased the amount of TCRzeta that accumulated in the rafts. These results suggest that CTLA-4 functions to regulate T cell signaling by controlling TCR accumulation and/or retention within this a critical component of the immunological synapse.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • CD3 Complex / metabolism
  • CTLA-4 Antigen
  • Gene Deletion
  • Humans
  • Immunoconjugates*
  • Jurkat Cells
  • Lymphocyte Activation
  • Membrane Microdomains / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CD3 Complex
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • antigen T cell receptor, zeta chain
  • Abatacept