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. 1. 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. 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: c.ma@garvan.org.au.
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. CONCLUSION: 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.
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. CONCLUSION: 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: Bethany A Pillay; Danielle T Avery; Joanne M Smart; Theresa Cole; Sharon Choo; Damien Chan; Paul E Gray; Katie Frith; Richard Mitchell; Tri Giang Phan; Melanie Wong; Dianne E Campbell; Peter Hsu; John B Ziegler; Jane Peake; Frank Alvaro; Capucine Picard; Jacinta Bustamante; Benedicte Neven; Andrew J Cant; Gulbu Uzel; Peter D Arkwright; Jean-Laurent Casanova; Helen C Su; Alexandra F Freeman; Nirali Shah; Dennis D Hickstein; Stuart G Tangye; Cindy S Ma Journal: JCI Insight Date: 2019-04-25
Authors: Caitlin Schneider; Connie Shen; Angelica A Gopal; Todd Douglas; Benjamin Forestell; Keith D Kauffman; Dakota Rogers; Patricio Artusa; Qian Zhang; Huie Jing; Alexandra F Freeman; Daniel L Barber; Irah L King; Maya Saleh; Paul W Wiseman; Helen C Su; Judith N Mandl Journal: Nat Immunol Date: 2020-10-05 Impact factor: 25.606