The cell-cell adhesion molecule carcinoembryonic antigen-related cellular adhesion molecule 1 inhibits IL-2 production and proliferation in human T cells by association with Src homology protein-1 and down-regulates IL-2 receptor.
The cell adhesion molecule, carcinoembryonic Ag-related cellular adhesion molecule 1, shown by others to both activate and inhibit T cell proliferation, exhibits a reciprocal relationship to IL-2R expression over the time course of activation of PBMCs, and upon Ab ligation, inhibits both the production of IL-2 and cell proliferation. Carcinoembryonic Ag-related cellular adhesion molecule 1 associates with CD3 and is found in lipid rafts of PBMCs, is phosphorylated on the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of the -4L isoform, and associates with Src homology protein-1, providing an explanation for its inhibitory activity. When the ITIM-containing -4L and non-ITIM-containing -4S isoforms are transfected into Jurkat cells that produce, but do not depend on IL-2 for growth, both IL-2 production and cell proliferation are differentially inhibited, demonstrating that the two isoforms signal via different pathways. When the two isoforms are transfected into Kit-225 cells that depend on IL-2 for growth, IL-2Rbeta and gamma, but not alpha subunits are down-regulated, and the -4L, but not the -4S isoform inhibits cell proliferation by 6-fold in an IL-2 dose-response study.
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Charng-Jui
CJ
Chen
John E
JE
Shively
D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017252:CD3 Complex / Q000378:metabolism; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D005677:G(M1) Ganglioside / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D053616:Janus Kinase 3; D019169:Jurkat Cells; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011940:Receptor Aggregation / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; C115335:CD3E protein, human; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D006131:Growth Inhibitors; D007106:Immune Sera; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D020033:Protein Isoforms; D015375:Receptors, Interleukin-2; D049452:Green Fluorescent Proteins; D005677:G(M1) Ganglioside; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases