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DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

Nature Immunology volume 13, pages 612–620 (2012)Cite this article

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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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Figure 1: Impaired antibody responses, inability to maintain serological memory and fewer memory B cells in DOCK8-deficient patients.
Figure 2: Impaired CpG-driven B cell proliferation and immunoglobulin production in response to CpG in DOCK8-deficient patients.
Figure 3: Normal CpG-driven upregulation of the expression of AICDA, CD23 and CD86, activation of NFκB, p38 and Rac1, and secretion of IL-6 in B cells from DOCK8-deficient patients.
Figure 4: CpG-induced DOCK8-dependent phosphorylation of STAT3 in B cells is essential for B cell proliferation and IgG production.
Figure 5: CpG-driven phosphorylation of STAT3 in B cells is dependent on Syk and requires TLR9 and MyD88.
Figure 6: DOCK8 mediates CpG activation of a Pyk2-Src-Syk-STAT3 cascade essential for B cell proliferation and differentiation.
Figure 7: DOCK8 associates with MyD88 and Pyk2 and undergoes Pyk2-mediated tyrosine phosphorylation and association with Src and/or Lyn after ligation of TLR9.

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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.).

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Author notes

  1. Haifa H Jabara and Douglas R McDonald: These authors contributed equally to this work.

Authors and 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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  1. Haifa H Jabara
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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.

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Correspondence to Raif S Geha.

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Jabara, H., McDonald, D., Janssen, E. et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol 13, 612–620 (2012). https://doi.org/10.1038/ni.2305

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