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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.

Original publication

DOI

10.1038/ni.1820

Type

Journal article

Journal

Nature immunology

Publication Date

12/2009

Volume

10

Pages

1283 - 1291

Addresses

John Curtin School of Medical Research and Australian Phenomics Facility, Australian National University, Australia.

Keywords

Synapses, Germinal Center, B-Lymphocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Guanine Nucleotide Exchange Factors, Sequence Alignment, Lymphocyte Activation, Antibody Formation, Amino Acid Sequence, Base Sequence, Protein Structure, Quaternary, Mutation, Models, Molecular, Molecular Sequence Data