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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Change history
24 March 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41590-022-01180-8
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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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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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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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DOI: https://doi.org/10.1038/ni.2305
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