Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T_H17 cell differentiation

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• 作者：Sevgi Keles ; MD^a ; ^b ; Louis Marie Charbonnier ; PhD^a ; Venkataraman Kabaleeswaran ; PhD^c ; Ismail Reisli ; MD^b ; Ferah Genel ; MD^d ; Nesrin Gulez ; MD^d ; Waleed Al-Herz ; MD^e ; Narayanaswamy Ramesh ; PhD^a ; Antonio Perez-Atayde ; MD^f ; Neslihan E. Karaca ; MD^g ; Necil Kutukculer ; MD^g ; Hao Wu ; PhD^a ; ^c ; Raif S. Geha ; MD^a ; Talal A. Chatila ; MD ; MSc^a ; ^{talal.chatila@childrens.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cell division cycle 42 ; dedicator of cytokinesis 8 ; guanine nucleotide exchange factor ; hyper-IgE syndrome ; mucocutaneous candidiasis ; suppressor of cytokine signaling 3 ; signal transducer and activator of transcription 3 ; TH17
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：138
• 期：5
• 页码：1384-1394.e2
• 全文大小：3417 K

文摘

The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of T_H17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear.

Objective

We sought to elucidate common mechanisms operating in the different forms of HIES.

Methods

We analyzed the differentiation of CD4⁺ T_H cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. T_H cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and T_H cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis.

Results

There was a profound block in the differentiation of DOCK8-deficient naive CD4⁺ T cells into T_H17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired T_H17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity–dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression.

Conclusion

DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent T_H17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES.