NTB-A, a new activating receptor in T cells that regulates autoimmune disease.
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.
Valdez
Patricia A
PA
Department of Immunology and Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
Wang
Hua
H
Seshasayee
Dhaya
D
van Lookeren Campagne
Menno
M
Gurney
Austin
A
Lee
Wyne P
WP
Grewal
Iqbal S
IS
D000818:Animals; D015703:Antigens, CD; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007141:Immunoglobulin Fc Fragments; D007136:Immunoglobulins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects
D015703:Antigens, CD; D002352:Carrier Proteins; D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C114953:SH2D1A protein, human; C000604060:SLAMF6 protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; C000604063:Slamf6 protein, mouse; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1