Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production

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Abstract
High-affinity and isotype-switched antibodies arise from germinal center reactions. Goodnow and colleagues identify the Rho guanine nucleotide–exchange factor DOCK8 as being essential for sustained B cell immune synapse formation in germinal centers and mature antibody responses. 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.