DOCK8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production
To illuminate genes and mechanisms for humoral immunity we performed 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 were loss-of-function mutations in Dedicator of Cytokinesis 8 (DOCK8). DOCK8 mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. DOCK8 mutation disrupted the concentration of ICAM-1 in the B cell immune synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to DOCK8 mutation provides evidence that organization of an immune synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.
|Authors||Randall, K. L.; Lambe, T.; Johnson, A.; Treanor, B.; Kucharska, E.; Domaschenz, H.; Whittle, B.; Tze, L. E.; Enders, A.; Crockford, T. L.; Bouriez-Jones, T.; Alston, D.; Cyster, J. G.; Lenardo, M. J.; Mackay, F.; Deenick, E. K.; Tangye, S. G.; Chan, T. D.; Camidge, T.; Brink, R.; Vinuesa, C. G.; Batista, F. D.; Cornall, R. J.; Goodnow, C. C.|
|Publisher Name||NATURE IMMUNOLOGY|
|DOI||ni.1820 [pii] 10.1038/ni.1820|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898472|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10348|