Abstract

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27+ memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src–kinase Syk–transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

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Acknowledgements

We thank F. Uckun (University of Southern California, Los Angeles) for SYKINH-61; R. Treisman (Cancer Research UK) for hemagglutinin-tagged MRTF-A; J.-L. Casanova (The Rockefeller University), A. Puel and C. Picard (Hopital Necker-Enfants Malades, France) for the MyD88-deficient EBV-B cell line; K. Eurich for technical assistance; A. Rambhatla and A. Chen for help in DNA sequencing; members of the Geha laboratory for discussions; J. Kagan and H. Oettgen for comments on the manuscript; and the patients and their families for donating blood. Supported by the US Public Health Service (P01AI076210, T32AI007512 and R01AI083503 to R.S.G.; R21AI087627 to T.A.C.; and K08AI076625 to D.R.M.), the Dubai Harvard Foundation for Medical Research (R.S.G. and L.D.N.), the Swiss National Science Foundation (PASMP3-127678/1 to M.R.), the Clinical Immunology Society (E.J.) and the Manton Foundation (E.J. and L.D.N.).

Author information

Author notes

    • Haifa H Jabara
    •  & Douglas R McDonald

    These authors contributed equally to this work.

Affiliations

  1. Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Haifa H Jabara
    • , Douglas R McDonald
    • , Erin Janssen
    • , Michel J Massaad
    • , Narayanaswamy Ramesh
    • , Arturo Borzutzky
    • , Ingrid Rauter
    • , Halli Benson
    • , Lynda Schneider
    • , Sachin Baxi
    • , Mike Recher
    • , Luigi D Notarangelo
    •  & Raif S Geha
  2. American University of Beirut, Beirut, Lebanon.

    • Rima Wakim
    •  & Ghassan Dbaibo
  3. Department of Pediatrics and Department of Internal Medicine, Division of Genetics, Endocrinology & Metabolism, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Majed Dasouki
  4. Department of Pediatrics, Allergy and Clinical Immunology Unit, Al-Sabah Hospital, Kuwait City, Kuwait.

    • Waleed Al-Herz
  5. Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.

    • Isil Barlan
    •  & Safa Baris
  6. Department of Pediatric Immunology, Ege University, Izmir, Turkey.

    • Necil Kutukculer
  7. Department of Pediatrics, University of Washington, Seattle, Washington, USA.

    • Hans D Ochs
  8. Pediatric Clinic and Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, Brescia, Italy.

    • Alessandro Plebani
  9. Agia Sophia Children's Hospital, Athens, Greece.

    • Maria Kanariou
  10. Institute of Medical Genetics, Centre National de la Recherche Scientifique, Unité Propre de Recherché 1142, University of Montpellier, Montpellier, France.

    • Gerard Lefranc
  11. Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Selcuk University, Konya, Turkey.

    • Ismail Reisli
    •  & Sevgi Keles
  12. Department of Medicine, University of Massachusetts, Worcester, Massachusetts, USA.

    • Katherine A Fitzgerald
    •  & Douglas Golenbock
  13. Department of Transfusion Medicine, Children's Hospital, Boston, Massachusetts, USA.

    • John Manis
  14. Division of Allergy and Immunology and Department of Pediatrics, University of California Los Angeles, Los Angeles, California, USA.

    • Sevgi Keles
    • , Reuben Ceja
    •  & Talal A Chatila

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Contributions

H.H.J., D.R.M., E.J., M.J.M., N.R., A.B., I.Ra., H.B. and M.R. did the experiments; L.S., S.B., R.W., G.D., M.D., W.A.-H., I.B., S.B., N.K., H.D.O., A.P., M.K., G.L. and I.Re. provided patient blood samples; K.A.F. and D.G. provided mice; J.M. and L.D.N. provided advice; S.K., R.C. and T.A.C. sequenced DNA; and H.H.J. and R.S.G. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Raif S Geha.

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https://doi.org/10.1038/ni.2305

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