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.
Department of Immunology and Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
Patricia A
PA
Valdez
Hua
H
Wang
Dhaya
D
Seshasayee
Menno
M
van Lookeren Campagne
Austin
A
Gurney
Wyne P
WP
Lee
Iqbal S
IS
Grewal
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