Dedicator of cytokinesis 8-deficient CD4(+) T cells are biased to a T(H)2 effector fate at the expense of T(H)1 and T(H)17 cells

作者：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^*

来源：Journal of Allergy and Clinical Immunology, 2017, 139(3): 933-949.

DOI：10.1016/j.jaci.2016.07.016

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

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 1 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 1 T cells were biased toward a T(H)2 type, and this was at the expense of T(H)1 and T(H)17 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 T(H)2 bias is likely to contribute to atopic disease, whereas defects in T(H)1 and T(H)17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.

• 出版日期2017-3
• 单位河北医科大学