Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells

Tangye, Stuart G., Pillay, Bethany, Randall, Katrina L., Avery, Danielle T., Tri Giang Phan, Gray, Paul, Ziegler, John B., Smart, Joanne M., Peake, Jane, Arkwright, Peter D., Hambleton, Sophie, Orange, Jordan, Goodnow, Christopher C., Uzel, Gulbu, Casanova, Jean-Laurent, Lugo Reyes, Saul Oswaldo, Freeman, Alexandra F., Su, Helen C. and Ma, Cindy S. (2017) Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells. Journal of Allergy and Clinical Immunology, 139 3: 933-949. doi:10.1016/j.jaci.2016.07.016


Author Tangye, Stuart G.
Pillay, Bethany
Randall, Katrina L.
Avery, Danielle T.
Tri Giang Phan
Gray, Paul
Ziegler, John B.
Smart, Joanne M.
Peake, Jane
Arkwright, Peter D.
Hambleton, Sophie
Orange, Jordan
Goodnow, Christopher C.
Uzel, Gulbu
Casanova, Jean-Laurent
Lugo Reyes, Saul Oswaldo
Freeman, Alexandra F.
Su, Helen C.
Ma, Cindy S.
Title Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells
Formatted title
Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells
Journal name Journal of Allergy and Clinical Immunology   Check publisher's open access policy
ISSN 1097-6825
0091-6749
Publication date 2017-03-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.jaci.2016.07.016
Open Access Status Not yet assessed
Volume 139
Issue 3
Start page 933
End page 949
Total pages 17
Place of publication Philadelphia, PA, United States
Publisher Mosby
Collection year 2018
Language eng
Formatted 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 characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated.

Objective: We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency.

Methods: We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets 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 healthy control subjects.

Results: DOCK8-deficient memory CD4+ T cells were biased toward a TH2 type, and this was at the expense of TH1 and TH17 cells. In vitro polarization 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 features of this disorder: the TH2 bias is likely to contribute to atopic disease, whereas defects in TH1 and TH17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.
Keyword Allergy
Atopic disease
CD4+ T-cell differentiation
Chronic mucocutaneous candidiasis
Dedicator of cytokinesis 8
TH2 skewing
Viral immunity
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Medicine Publications
 
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