title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia. Electronic address: s.tangye@garvan.org.au.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia.
authors.forename: Bethany
authors.initials: B
authors.lastname: Pillay
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Acton, Australia; Australian National University Medical School, Australian National University, Acton, Australia.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Randall
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia.
authors.forename: Tri Giang
authors.initials: TG
authors.lastname: Phan
authors.affiliation: University of New South Wales School of Women's and Children's Health, Randwick, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gray
authors.affiliation: University of New South Wales School of Women's and Children's Health, Randwick, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Ziegler
authors.affiliation: Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smart
authors.affiliation: University of Queensland and Lady Cilento Children's Hospital, Brisbane, Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Peake
authors.affiliation: University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.affiliation: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine; the Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, and the Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors.forename: Jordan
authors.initials: J
authors.lastname: Orange
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.
authors.forename: Saul Oswaldo
authors.initials: SO
authors.lastname: Lugo Reyes
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia. Electronic address: c.ma@garvan.org.au.
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
mesh_terms: D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D000485:Allergens; D016207:Cytokines; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007073:Immunoglobulin E
keywords: CD4(+) T-cell differentiation; Dedicator of cytokinesis 8; T(H)2 skewing; allergy; atopic disease; chronic mucocutaneous candidiasis; viral immunity