MyD-1 (SIRPalpha) regulates T cell function in the absence of exogenous danger signals, via a TNFalpha-dependent pathway.
Signal inhibitory regulatory proteins are a family of transmembrane glycoproteins involved in the negative regulation of receptor tyrosine kinase signaling pathways. MyD-1 is a recently described member of this family. In this report we have assessed the function of MyD-1 in regulating T cell function utilizing an anti-MyD-1-specific monoclonal antibody (mAb). We show that ligating MyD-1 on antigen-presenting cells (APC) inhibits subsequent T cell activation induced by either anti-CD3 mAb or by allogeneic APC but has no effect on responses to either tuberculin purified protein derivative or tetanus toxoid antigens. Moreover, we show that the inhibition of T cell responses is not due to any change of costimulatory molecule expression on APC. We observed that the production of TNFalpha, a cytokine that we have earlier identified as important in the mechanism of MyD-1 immune regulation, is inhibited by cross-linking of MyD-1. We further show that TNFalpha is critically important in the regulation of T cell responses in the absence of danger signals, and indeed addition of TNFalpha can overcome the inhibitory effects of anti-MyD-1 antibody. This information may lead to a better understanding of the regulation of T cell responses in the absence of danger and therefore offer a possible therapeutic target to modulate aberrant immune responses.
Edward Jenner Institute for Vaccine Research, Compton, Newbury, GB.
Vanshree
V
Patel
Rosemary E
RE
Smith
Alessandro
A
Serra
Gareth
G
Brooke
Christopher J
CJ
Howard
Kevin P
KP
Rigley
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000276:immunology*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D017252:CD3 Complex / Q000276:immunology; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D039842:Neural Cell Adhesion Molecule L1; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013744:Tetanus Toxin / Q000276:immunology; D014373:Tuberculin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D017252:CD3 Complex; C497964:CD86 protein, human; D003432:Cross-Linking Reagents; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D011971:Receptors, Immunologic; D013744:Tetanus Toxin; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens