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Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2004 Mar 15; Vol. 172 (6), pp. 3535-43. - Publication Year :
- 2004
-
Abstract
- Carcinoembryonic Ag-related cellular adhesion molecule 1 (CEACAM1) represents a group of transmembrane protein isoforms that consist of variable numbers of extracellular Ig-like domains together with either a long cytoplasmic (cyt) tail containing two immunoreceptor tyrosine-based inhibitory motifs or a unique short cyt tail. Although CEACAM1 has been reported to be expressed on the surface of T lymphocytes upon activation, its roles in T cell regulation are controversial due to the lack of functional characterization of each individual CEACAM1 isoform. We thus cotransfected Jurkat T cells with CEACAM1 isoform-encoding constructs and an IL-2 promoter-bearing plasmid or a small interference RNA targeting src homology domain 2 containing phosphatase 1. In a luciferase reporter assay and through measurements of cytokine secretion (IL-2, IL-4, and IFN-gamma), CEACAM1 containing either a long or a short cyt tail inhibited or costimulated, respectively, TCR/CD3 complex plus CD28 mediated activation with the inhibitory functions of the long cyt tail dominating. The inhibitory function of CEACAM1, was dependent upon src homology domain 2 containing phosphatase 1 activity, required both tyrosine residues within the immunoreceptor tyrosine-based inhibitory motif domains of the cyt tail and was mediated through the mitogen-activated protein kinase pathway. CEACAM1-mediated inhibition could be functionally reconstituted by incubation of PBMC with either a CEACAM1-specific mAb or CEACAM1-Fc fusion protein in the presence of an allogeneic or mitogenic stimulus, respectively. These studies indicate that the long and short cyt tails of CEACAM1 serve as inhibitory and costimulatory receptors, respectively, in T cell regulation.
- Subjects :
- Antibodies, Monoclonal pharmacology
CD28 Antigens immunology
CD3 Complex immunology
Cells, Cultured
Cytoplasm immunology
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Genes, Reporter
Humans
Intracellular Signaling Peptides and Proteins
JNK Mitogen-Activated Protein Kinases
Jurkat Cells
Ligands
Mitogen-Activated Protein Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinases metabolism
NFATC Transcription Factors
Phosphorylation
Protein Isoforms physiology
Protein Phosphatase 1
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases physiology
Receptors, Immunologic physiology
T-Lymphocytes enzymology
Transcription Factor AP-1 antagonists & inhibitors
Transcription Factor AP-1 genetics
Transcription Factor AP-1 metabolism
Transcription Factors antagonists & inhibitors
Transcription Factors genetics
Transcription Factors metabolism
Transfection
Antigens, CD physiology
Antigens, Differentiation physiology
Antigens, Neoplasm physiology
Cell Adhesion Molecules physiology
Down-Regulation immunology
Immunosuppressive Agents pharmacology
Lymphocyte Activation immunology
Nuclear Proteins
T-Lymphocytes immunology
T-Lymphocytes metabolism
Up-Regulation immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 172
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 15004154
- Full Text :
- https://doi.org/10.4049/jimmunol.172.6.3535