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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

Nat Immunol

Publication Date

12/2009

Volume

10

Pages

1283 - 1291

Keywords

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