title: Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production.
abstract: To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.
authors.affiliation: John Curtin School of Medical Research and Australian Phenomics Facility, Australian National University, Australia.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Randall
authors.forename: Teresa
authors.initials: T
authors.lastname: Lambe
authors.forename: Andy L
authors.initials: AL
authors.lastname: Johnson
authors.forename: Andy
authors.initials: A
authors.lastname: Johnson
authors.forename: Bebhinn
authors.initials: B
authors.lastname: Treanor
authors.forename: Edyta
authors.initials: E
authors.lastname: Kucharska
authors.forename: Heather
authors.initials: H
authors.lastname: Domaschenz
authors.forename: Belinda
authors.initials: B
authors.lastname: Whittle
authors.forename: Lina E
authors.initials: LE
authors.lastname: Tze
authors.forename: Anselm
authors.initials: A
authors.lastname: Enders
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Crockford
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Bouriez-Jones
authors.forename: Duncan
authors.initials: D
authors.lastname: Alston
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Tyani D
authors.initials: TD
authors.lastname: Chan
authors.forename: Tahra
authors.initials: T
authors.lastname: Camidge
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D013569:Synapses / Q000276:immunology*
chemical_list: C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors