Abstract
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.
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Change history
04 December 2009
In the version of this article initially published, the third author's name is missing the middle initial. The correct name is Andy L Johnson. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank M. Townsend, D. Howard, H. Ferry and C. Gillespie for technical assistance; the staff of the Australian National University Bioscience Division and Oxford Biomedical Services Unit for animal husbandry; the Australian Phenomics Facility genotyping and mapping team for genetic analysis, R. Rigby, B. Balakishnan and L. Beaton (Australian National University) for advice and reagents; J. Cannons and P. Schwartzberg (National Institutes of Health) for B cell–T cell conjugation methods and SAP-deficient mice; C. Jenne, S. Watson and T. Pham (University of California, San Francisco) for collaboration; R. Schwartz (National Institutes of Health) for support with advice and reagents; and H. Su (National Institutes of Health) for sharing findings about human DOCK8 deficiency before publication. Supported by the Wellcome Trust (R.J.C. and C.C.G.), the Australian Research Council (C.C.G.), the National Health and Medical Research Council (C.C.G., R.B., S.G.T., C.G.V., F.M., K.L.R., L.E.T. and E.K.D.), the Medical Research Council (T.L. and R.J.C.), The Ramaciotti Foundation (A.E. and C.C.G.), Deutsche Forschungsgemeinschaft (A.E.), Cancer Research UK (F.D.B.), the Andrew McMichael Trust Fund (R.J.C.) and the National Institute for Health Research Biomedical Research Centre Programme (R.J.C.).
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T.L., K.L.R., A.L.J., T.B.-J. and B.W. mapped and identified the mutations; K.L.R. analyzed pri and complementation crosses with E.K., H.D., L.E.T. and A.E.; T.L. analyzed cpm with T.L.C., A.L.J., T.B.-J., D.A. and J.G.C.; B.T. and F.D.B. did synapse analysis; M.J.L. supervised early experiments on cpm by A.L.J.; F.M. and K.L.R. analyzed the effects of the BAFF transgene; E.K.D. and S.G.T. analyzed SAP-dependent B cell–T cell conjugation; K.L.R., T.D.C., T.C. and R.B. analyzed GC response in the SWHEL adoptive-transfer system; C.G.V. and E.K. designed and established the genetic screen and identified cpm and pri founders; C.C.G. and R.J.C. initiated and contributed to all aspects of study design and interpretation; and K.L.R., T.L., R.J.C. and C.C.G. wrote the paper in consultation with all coauthors.
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Randall, K., Lambe, T., Johnson, A. et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat Immunol 10, 1283–1291 (2009). https://doi.org/10.1038/ni.1820
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DOI: https://doi.org/10.1038/ni.1820
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