Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP-70

J Immunol. 2008 May 1;180(9):6085-93. doi: 10.4049/jimmunol.180.9.6085.

Abstract

The long cytoplasmic tail (CT) isoforms of carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1) are expressed on activated human T cells and possess two ITIM motifs in the CT. These isoforms of CEACAM1 are inhibitory for T cell responses initiated by the TCR/CD3 complex with the inhibition dependent upon the ITIMs of CEACAM1 and Src homology 2 domain-containing phosphatase 1 (SHP-1). However, the mechanism by which this inhibition occurs in T cells is unknown. We demonstrate here that the Src family kinase, Lck, and the ability of CEACAM1 to bind homophilically are required for the ITIM phosphorylation of CEACAM1 that is a prerequisite for CEACAM1 association with SHP-1. We further show that CEACAM1 associates with and recruits SHP-1 to the TCR/CD3 complex leading to decreased phosphorylation of CD3-zeta and ZAP-70 and consequently decreased activation of the elements downstream of ZAP-70. This is physiologically relevant because extinction of SHP-1 expression or blockade of homophilic binding by CEACAM1 using a Fab that specifically recognizes the homophilic binding region of human CEACAM1 increases the cytolytic function initiated by the TCR/CD3 complex. These studies show that long CT isoforms of CEACAM1 orchestrate an inhibitory program that abrogates extremely proximal events downstream of the TCR/CD3 complex by focusing on the activation of ZAP-70.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs / immunology
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • Binding Sites / immunology
  • CD3 Complex / immunology*
  • CD3 Complex / metabolism
  • Cell Adhesion Molecules / immunology*
  • Cell Adhesion Molecules / metabolism
  • Humans
  • Immunoglobulin Fab Fragments / metabolism
  • Immunoglobulin Fab Fragments / pharmacology
  • Jurkat Cells
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Binding / immunology
  • Protein Isoforms / immunology
  • Protein Isoforms / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

  • Antigens, CD
  • CD3 Complex
  • CD66 antigens
  • Cell Adhesion Molecules
  • Immunoglobulin Fab Fragments
  • Protein Isoforms
  • Receptors, Antigen, T-Cell
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6