Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production.
Randall KL., Lambe T., Johnson AL., Treanor B., Kucharska E., Domaschenz H., Whittle B., Tze LE., Enders A., Crockford TL., Bouriez-Jones T., Alston D., Cyster JG., Lenardo MJ., Mackay F., Deenick EK., Tangye SG., Chan TD., Camidge T., Brink R., Vinuesa CG., Batista FD., Cornall RJ., Goodnow CC.
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.