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

Nature Immunology volume 10, pages 1283–1291 (2009)Cite this article

A Corrigendum to this article was published on 01 July 2010

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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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Figure 1: Identification of two independent, noncomplementing N-ethyl-N-nitrosourea–mutant mouse strains with humoral immunodeficiency characterized by failure to sustain a primary immune response and failure of maturation of the antibody response.
Figure 2: Analysis of splenic and peritoneal lymphocyte subsets.
Figure 3: Independent Dock8 mutations in pri and cpm mouse strains.
Figure 4: Dock8 mutation causes an intrinsic defect in GC B cells.
Figure 5: DOCK8-mutant B cells undergo normal T cell–dependent activation, switching and initial differentiation into GC cells in vivo.
Figure 6: Intrinsic failure of DOCK8-mutant GC B cells to persist or undergo affinity maturation.
Figure 7: Dock8 mutations disrupt the formation of the B cell immunological synapse but not other aspects of signaling through the B cell antigen receptor.

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  • 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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Author notes

  1. Katrina L Randall, Teresa Lambe, Richard J Cornall and Christopher C Goodnow: These authors contributed equally to this work.

Authors and Affiliations

  1. John Curtin School of Medical Research and Australian Phenomics Facility, Australian National University, Australia

    Katrina L Randall, Edyta Kucharska, Heather Domaschenz, Belinda Whittle, Lina E Tze, Anselm Enders, Carola G Vinuesa & Christopher C Goodnow

  2. Department of Immunology, The Canberra Hospital, Garran, Australian Capital Territory, Australia

    Katrina L Randall

  3. Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK

    Teresa Lambe, Andy L Johnson, Tanya L Crockford, Tiphaine Bouriez-Jones, Duncan Alston & Richard J Cornall

  4. Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA

    Andy L Johnson

  5. Laboratory of Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA

    Bebhinn Treanor & Facundo D Batista

  6. Cancer Research UK, London Research Institute, Lincoln's Inn Fields, London, UK

    Jason G Cyster

  7. Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, California, USA

    Michael J Lenardo

  8. Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia

    Fabienne Mackay

  9. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    Elissa K Deenick, Stuart G Tangye, Tyani D Chan, Tahra Camidge & Robert Brink

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Contributions

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.

Corresponding authors

Correspondence to Richard J Cornall or Christopher C Goodnow.

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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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