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

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 3; pp. 933 - 949
• Main Authors: Tangye, Stuart G., Pillay, Bethany, Randall, Katrina L., Avery, Danielle T., Phan, Tri Giang, 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.
• Format: Journal Article
• Language: English
• Published: St. Louis Elsevier Inc 01.03.2017; Elsevier Limited
• Subjects: allergy; Antigens; Asthma; atopic disease; Bias; CD4+ T-cell differentiation; chronic mucocutaneous candidiasis; Cytokines; Cytomegalovirus; Dedicator of cytokinesis 8; Defects; Dermatophagoides pteronyssinus; Disease; Eczema; Food; Food allergies; Herpes viruses; Infections; Lymphocytes; Lymphoma; Mutation; Stem cells; T cell receptors; TH2 skewing; Transplants & implants; viral immunity; Viral infections; Dedicator of cytokinesis 8; TCR; DOCK8; RORC; TH2 skewing; chronic mucocutaneous candidiasis; HPV; atopic disease; TFH; CMC; ICOS; PMA; Treg; CD4+ T-cell differentiation; allergy; CFSE; HSV; PID; T-bet; viral immunity; STAT; APC; AR-HIES; PE; TAE; NK; PD-1; TEM; TCM
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.07.016

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. 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. 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. 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. 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.