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

Stuart G Tangye; Bethany Pillay; Katrina L Randall; Danielle T Avery; Tri Giang Phan; Paul Gray; John B Ziegler; Joanne M Smart; Jane Peake; Peter D Arkwright; Sophie Hambleton; Jordan Orange; Christopher C Goodnow; Gulbu Uzel; Jean-Laurent Casanova; Saul Oswaldo Lugo Reyes; Alexandra F Freeman; Helen C Su; Cindy S Ma

doi:10.1016/j.jaci.2016.07.016

Dedicator of cytokinesis 8-deficient CD4⁺ T cells are biased to a T_H2 effector fate at the expense of T_H1 and T_H17 cells

J Allergy Clin Immunol. 2017 Mar;139(3):933-949. doi: 10.1016/j.jaci.2016.07.016. Epub 2016 Aug 20.

Authors

Stuart G Tangye¹, Bethany Pillay², Katrina L Randall³, Danielle T Avery⁴, Tri Giang Phan², Paul Gray⁵, John B Ziegler⁵, Joanne M Smart⁶, Jane Peake⁷, Peter D Arkwright⁸, Sophie Hambleton⁹, Jordan Orange¹⁰, Christopher C Goodnow², Gulbu Uzel¹¹, Jean-Laurent Casanova¹², Saul Oswaldo Lugo Reyes¹³, Alexandra F Freeman¹¹, Helen C Su¹⁴, Cindy S Ma¹⁵

Affiliations

¹ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia. Electronic address: [email protected].
² Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia.
³ Department of Immunology, John Curtin School of Medical Research, Acton, Australia; Australian National University Medical School, Australian National University, Acton, Australia.
⁴ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
⁵ University of New South Wales School of Women's and Children's Health, Randwick, Australia.
⁶ Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.
⁷ University of Queensland and Lady Cilento Children's Hospital, Brisbane, Australia.
⁸ University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
⁹ Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
¹⁰ 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.
¹¹ Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹² 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.
¹³ Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.
¹⁴ Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹⁵ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia. Electronic address: [email protected].

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.

MeSH terms

Adolescent
Adult
Allergens / immunology
Child
Child, Preschool
Cytokines / immunology
Female
Guanine Nucleotide Exchange Factors / deficiency*
Guanine Nucleotide Exchange Factors / immunology
Humans
Immunoglobulin E / blood
Immunologic Deficiency Syndromes / immunology*
Leukocytes, Mononuclear / immunology
Male
T-Lymphocytes / immunology*
Young Adult

Substances

Allergens
Cytokines
DOCK8 protein, human
Guanine Nucleotide Exchange Factors
Immunoglobulin E

Abstract

MeSH terms

Substances

Grants and funding