title: Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease.
abstract: The DENN domain is an evolutionary conserved protein module found in all eukaryotes and serves as an exchange factor for Rab-GTPases to regulate diverse cellular functions. Variants in DENND1B are associated with development of childhood asthma and other immune disorders. To understand how DENND1B may contribute to human disease, Dennd1b(-/-) mice were generated and exhibit hyper-allergic responses following antigen challenge. Dennd1b(-/-) TH2, but not other TH cells, exhibit delayed receptor-induced T cell receptor (TCR) downmodulation, enhanced TCR signaling, and increased production of effector cytokines. As DENND1B interacts with AP-2 and Rab35, TH2 cells deficient in AP-2 or Rab35 also exhibit enhanced TCR-mediated effector functions. Moreover, human TH2 cells carrying asthma-associated DENND1B variants express less DENND1B and phenocopy Dennd1b(-/-) TH2 cells. These results provide a molecular basis for how DENND1B, a previously unrecognized regulator of TCR downmodulation in TH2 cells, contributes to asthma pathogenesis and how DENN-domain-containing proteins may contribute to other human disorders.
authors.affiliation: Department of Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Chiao-Wen
authors.initials: CW
authors.lastname: Yang
authors.affiliation: Department of Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Caroline D
authors.initials: CD
authors.lastname: Hojer
authors.affiliation: Department of Translational Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Translational Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Human Genetics, Genentech, One DNA Way, South San Francisco, CA 94080, USA; Department of Bioinformatics and Computational Biology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Wuster
authors.affiliation: Department of Translational Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Human Genetics, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Yaspan
authors.affiliation: Research, Genentech, One DNA Way, South San Francisco, CA 94080, USA. Electronic address: acc@gene.com.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D016207:Cytokines; C546321:DENND1B protein, human; C000607952:DENND1B protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D011948:Receptors, Antigen, T-Cell; C543587:Rab35 protein, mouse; D020691:rab GTP-Binding Proteins