NTB-A, a new activating receptor in T cells that regulates autoimmune disease.

Abstract	The CD28 co-stimulatory pathway is well established for T cell activation; however, results from CD28 -/- mice suggest the existence of additional co-stimulatory pathways. Here we report the further characterization of a new member of the CD2 superfamily, NTB-A, important in T cell co-stimulation. NTB-A is expressed on T cells, and its expression is up-regulated on activated cells. Triggering of NTB-A with monoclonal antibodies in the absence of CD28 signals leads to T cell proliferation and interferon-gamma secretion but not interleukin-4. Cross-linking of NTB-A also induces phosphorylation of NTB-A and the association of SAP (SLAM-associated protein), the protein absent in X-linked lymphoproliferative disease. T helper cells differentiated by cross-linking NTB-A and CD3 developed predominantly into Th1 cells not Th2 cells. In vivo blocking of NTB-A interactions with its ligands by using soluble NTB-A-Fc fusion protein inhibits B cell isotype switching to IgG2a and IgG3, commonly induced by Th1-type cytokines. Most important, treatment of mice with NTB-A-Fc delays the onset of antigen-induced experimental allergic encephalomyelitis in myelin basic protein-T cell receptor transgenic mice, suggesting a role in T cell-mediated autoimmune disease. Regulation of interferon-gamma secretion, and not interleukin-4 in vitro, as well as inhibition of Th1 cell-induced isotype switching and attenuation of experimental allergic encephalomyelitis indicate that NTB-A is important for Th1 responses. The observation that cross-linking of NTB-A induces T cell activation, expansion, and Th1-type cytokine production suggests NTB-A is a novel co-stimulatory receptor. The identification of NTB-A as a regulator of T cell response paves the way to provide novel therapeutic approaches for modulation of the immune response.
Authors	Patricia A Valdez, Hua Wang, Dhaya Seshasayee, Menno van Lookeren Campagne, Austin Gurney, Wyne P Lee, Iqbal S Grewal
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 18 Pg. 18662-9 (Apr 30 2004) ISSN: 0021-9258 [Print] United States
PMID	14988414 (Publication Type: Journal Article)
Chemical References	Antigens, CD Carrier Proteins Glycoproteins Immunoglobulin Fc Fragments Immunoglobulins Intracellular Signaling Peptides and Proteins Receptors, Antigen, T-Cell Receptors, Cell Surface Recombinant Fusion Proteins SH2D1A protein, human SLAMF6 protein, human Sh2d1a protein, mouse Signaling Lymphocytic Activation Molecule Associated Protein Signaling Lymphocytic Activation Molecule Family Slamf6 protein, mouse Signaling Lymphocytic Activation Molecule Family Member 1
Topics	Animals Antigens, CD Autoimmune Diseases (drug therapy, immunology) Carrier Proteins (metabolism) Encephalomyelitis, Autoimmune, Experimental (drug therapy) Glycoproteins (administration & dosage, immunology, metabolism) Humans Immunoglobulin Class Switching (drug effects) Immunoglobulin Fc Fragments Immunoglobulins (administration & dosage, immunology, metabolism) Intracellular Signaling Peptides and Proteins Mice Mice, Transgenic Phosphorylation Receptors, Antigen, T-Cell (administration & dosage, immunology, metabolism) Receptors, Cell Surface Recombinant Fusion Proteins (pharmacology) Signaling Lymphocytic Activation Molecule Associated Protein Signaling Lymphocytic Activation Molecule Family Signaling Lymphocytic Activation Molecule Family Member 1 T-Lymphocytes (immunology, metabolism) Th1 Cells (drug effects)

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