title: SLy2 controls the antibody response to pneumococcal vaccine through an IL-5Rα-dependent mechanism in B-1 cells.
abstract: The adaptor protein SLy2 (Src homology domain 3 lymphocyte protein 2) is located on human chromosome 21 and was reported to be among a group of genes amplified in Down's syndrome (DS) patients. DS patients characteristically show an impaired immunity to pneumococcal infections. However, molecular mechanisms linking gene amplifications with specific DS phenotypes remain elusive. To investigate the effect of SLy2 gene amplification on the mammalian immune system, we studied SLy2 overexpressing transgenic-SLy2 (TG) mice. We found that baseline immunoglobulin M (IgM) levels as well as IgM responses following Pneumovax immunizations were reduced in TG mice. Moreover, B-1 cells, the major natural IgM-producing population in mice, were reduced in the peritoneal cavity of TG mice, while other immune cell compartments were unaltered. Mechanistically, SLy2 overexpression attenuated the expression of the IL-5 receptor α chain on B-1 cells, resulting in decreased B-1 cell numbers and decreased differentiation into Ab-secreting cells. Since B-1 cells essentially contribute to immunity against Streptococcus pneumoniae, the present study provides a novel molecular link between SLy2 expression and pneumococcal-specific IgM responses in vivo. These studies suggest that the adaptor protein SLy2 is a potential future target for immunomodulatory strategies for pneumococcal infections.
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany.
authors.forename: Fee
authors.initials: F
authors.lastname: Schmitt
authors.forename: Daniel
authors.initials: D
authors.lastname: Schäll
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bucher
authors.forename: Theresa Isabell
authors.initials: TI
authors.lastname: Schindler
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Tilo
authors.initials: T
authors.lastname: Biedermann
authors.forename: Michael
authors.initials: M
authors.lastname: Zemlin
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D056724:Immunity, Humoral / Q000187:drug effects; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis*; D053666:Interleukin-5 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000008:administration & dosage; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D053666:Interleukin-5 Receptor alpha Subunit; D022242:Pneumococcal Vaccines; C000596182:SLy2 protein, mouse; C527275:interleukin-5- receptor alpha, mouse
keywords: B-1 cells; IL-5R; IgM; Pneumococcal polysaccharides; SLy2