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

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 T_H2 type, and this was at the expense of T_H1 and T_H17 cells. In vitro polarization of DOCK8-deficient naive CD4⁺ T cells revealed the T_H2 bias and T_H17 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 T_H2 bias is likely to contribute to atopic disease, whereas defects in T_H1 and T_H17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.

Keywords: CD4(+) T-cell differentiation; Dedicator of cytokinesis 8; T(H)2 skewing; allergy; atopic disease; chronic mucocutaneous candidiasis; viral immunity.