DOCK8-Deficient CD4+ T Cells are Biased to a Th2 Effector Fate at the Expense of Th1 and Th17 Cells

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Stuart G. Tangye, Bethany Pillay, Katrina L. Randall, Danielle T. Avery, Tri Giang Phan, Paul Gray, John B. Ziegler, Joanne M. Smart, Jane Peake, Peter D. Arkwright, Sophie Hambleton, Jordan Orange, Christopher C. Goodnow, Gulbu Uzel, Jean-Laurent Casanova, Saul Oswaldo Lugo Reyes, Alexandra F. Freeman, Helen C. Su, Cindy S. Ma
BackgroundDedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterised by recurrent cutaneous infections, elevated serum IgE, and severe atopic disease including anaphylaxis to foods. However, the contribution of defects in CD4⁺ T cells to disease pathogenesis in these patients has not been thoroughly investigated.ObjectiveTo investigate the phenotype and function of DOCK8-deficient CD4⁺ T cells to determine (1) intrinsic and extrinsic CD4⁺ T cell defects (2) how defects account for the clinical features of DOCK8 deficiency.MethodsWe performed indepth analysis of the CD4⁺ T cell compartment of DOCK8-deficient patients. We enumerated subets of CD4⁺ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and normal controls.ResultsDOCK8-deficient memory CD4⁺ T cells were biased towards a Th2 type, and this was at the expense of Th1 and Th17 cells. In vitro polarisation of DOCK8-deficient naive CD4⁺ T cells revealed the Th2 bias and Th17 defect to be T-cell intrinsic. Examination of allergen specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens, but not house dust mites.ConclusionInvestigations into the DOCK8-deficient CD4⁺ T cells provided an explanation for some of the clinical signs of this disorder - the Th2 bias is likely to contribute to atopic disease, while defects in Th1 and Th17 cells compromise anti-viral and anti-fungal immunity, respectively explaining the infectious susceptibility of DOCK8-deficient patients.

Teaser

DOCK8-deficient CD4⁺ T cells exhibit dysregulated cytokine responses, with exaggerated production of Th2 cytokines, and impaired production of Th1 and Th17 cytokines. Collectively these findings provide explanations for some of the clinical features of DOCK8 deficiency, such as eczema and food allergies, and recurrent viral and microbial infections.


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