CD19 controls Toll-like receptor 9 responses in human B cells

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Morbach, Henner¹  Schickel, Jean-Nicolas¹  Cunningham-Rundles, Charlotte²  Conley, Mary Ellen³  Reisli, Ismail⁴  Luis Franco, Jose⁵  Meffre, Eric¹ 

[1] Yale Univ, Sch Med, Dept Immunobiol, 300 George St, New Haven, CT 06511 USA

[2] Mt Sinai Med Ctr, Dept Med, New York, NY 10029 USA

[3] Univ Tennessee, Coll Med, Dept Pediat, Memphis, TN USA

[4] Selcuk Univ, Meram Med Fac, Dept Immunol & Allergy, Konya, Turkey

[5] Univ Antioquia, Grp Primary Immunodeficiencies, Medellin, Colombia

关键词: B cells;    Toll-like receptor 9;    CD19;    phosphoinositide 3-kinase;    Bruton tyrosine kinase;    AKT;    common variable immunodeficiency;   

DOI  :  10.1016/j.jaci.2015.08.040

来源: Elsevier

【 摘 要 】

Background: CD19 is a B cell-specific molecule that serves as a major costimulatory molecule for amplifying B-cell receptor (BCR) responses. Biallelic CD19 gene mutations cause common variable immunodeficiency in human subjects. BCR- and Toll-like receptor (TLR) 9-induced B-cell responses are impaired in most patients with common variable immunodeficiency. Objective: We sought to analyze whether CD19 is required for TLR9 function in human B cells. Methods: Expression of surface activation markers was assessed after anti-IgM or CpG stimulation by using flow cytometry on B cells from patients with 1 or 2 defective CD19 alleles, which decrease or abrogate CD19 expression, respectively. The phosphorylation or interaction of signaling molecules was analyzed by using phospho flow cytometry, immunoblotting, or co-immunoprecipitation in CD19-deficient or control B cells and in a B-cell line in which CD19 has been knocked down with lentivirus-transduced short hairpin RNA. Results: B cells from subjects with 1 or 2 defective CD19 alleles showed defective upregulation in vitro of CD86, transmembrane activator and CAML interactor (TACI), and CD23 activation markers after TLR9 stimulation. TLR9 ligands normally induce phosphorylation of CD19 through myeloid differentiation primary response gene-88 (MYD88)/proline-rich tyrosine kinase 2 (PYK2)/LYN complexes, which allows recruitment of phosphoinositide 3-kinase (PI3K) and phosphorylation of Bruton tyrosine kinase (BTK) and AKT in human B cells with a different kinetic than that of BCRs. In addition, inhibition of PI3K, AKT, or BTK, as well as BTK deficiency, also resulted in TLR9 activation defects in B cells similar to those in patients with CD19 deficiency. Conclusion: CD19 is required for TLR9-induced B-cell activation. Hence CD19/PI3K/AKT/BTK is an essential axis integrating BCRs and TLR9 signaling in human B cells.

【 授权许可】

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