DOCK8 Regulates STAT3 Activation and Promotes Th17 Cell Differentiation

Publication date: Available online 24 May 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Sevgi Keles, Louis Marie Charbonnier, Venkataraman Kabaleeswaran, Ismail Reisli, Ferah Genel, Nesrin Gulez, Waleed Al-Herz, Narayanaswamy Ramesh, Antonio Perez-Atayde, Neslihan Karaca Eeder, Necil Kutukculer, Hao Wu, Raif S. Geha, Talal A. Chatila
BackgroundThe autosomal recessive hyper IgE syndrome (AR-HIES) due to Dedicator Of Cytokinesis 8 (DOCK8) deficiency shares clinical features with the autosomal dominant HIES (AD-HIES) due to Signal Transducer and Activator of Transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, suggestive of Th17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear.ObjectiveWe sought to elucidate common mechanisms operative in the different forms of HIES.Experimental DesignWe analyzed the differentiation of CD4⁺ T helper (Th) cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells.MethodsTh cell differentiation was analyzed by ELISA, flow cytometry and real time PCR measurements of cytokines and Th cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by flow cytometry, immunofluorescence, co-immunoprecipitation and gene expression analysis.ResultsThere was a profound block in the differentiation of DOCK8-deficient naïve CD4⁺ T cells into Th17 cells. A missense mutation that disrupts DOCK8 guanine exchange factor (GEF) activity while sparing protein expression also impaired Th17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, while 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.ConclusionDOCK8 interacts with STAT3, regulates its activation and the outcome of STAT3-dependent Th17 differentiation. These findings may explain the phenotypic overlap between DOCK8 deficiency and AD-HIES.



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