Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function.
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.
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Daohong
D
Chen
Hideki
H
Iijima
Takashi
T
Nagaishi
Atsushi
A
Nakajima
Sara
S
Russell
Raktima
R
Raychowdhury
Victor
V
Morales
Christopher E
CE
Rudd
Nalan
N
Utku
Richard S
RS
Blumberg
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000502:physiology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D017930:Genes, Reporter; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D020033:Protein Isoforms / Q000502:physiology; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases