Dedicator of cytokinesis 8–deficient CD41 T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells

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 Arkwright, Sophie Hambleton, Jordan S. Orange, Christopher C. Goodnow, Gulbu Uzel, Jean Laurent Casanova, Saul Oswaldo Lugo Reyes, Alexandra Freeman, Helen C. Su, Cindy S Ma

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Dedicator 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.

OBJECTIVE: To 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.

METHODS: We 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.

RESULTS: DOCK8-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.

CONCLUSION: Investigations 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.

Original languageEnglish
Pages (from-to)933-949
Number of pages17
JournalThe Journal of allergy and clinical immunology
Volume139
Issue number3
Early online date20 Aug 2016
DOIs
Publication statusPublished - Mar 2017

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