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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Tangye, Stuart G.^1,2  Pillay, Bethany^1,2  Randall, Katrina L.^3,4  Avery, Danielle T.¹  Tri Giang Phan^1,2  Gray, Paul⁵  Ziegler, John B.⁵  Smart, Joanne M.⁶  Peake, Jane^7,8  Arkwright, Peter D.⁹  Hambleton, Sophie^10,11  Orange, Jordan^12,13,14,15  Goodnow, Christopher C.^1,2  Uzel, Gulbu¹⁶  Casanova, Jean-Laurent^18,19,20,21  Lugo Reyes, Saul Oswaldo²²  Freeman, Alexandra F.¹⁶  Su, Helen C.¹⁷  Ma, Cindy S.^1,2 

[1] Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW, Australia

[2] Univ New South Wales, St Vincents Clin Sch, Darlinghurst, NSW, Australia

[3] John Curtin Sch Med Res, Dept Immunol, Acton, ACT, Australia

[4] Australian Natl Univ, Sch Med, Acton, ACT, Australia

[5] Univ New South Wales, Sch Womens & Childrens Hlth, Randwick, NSW, Australia

[6] Royal Childrens Hosp Melbourne, Dept Allergy & Immunol, Parkville, Vic, Australia

[7] Univ Queensland, Brisbane, Qld, Australia

[8] Lady Cilento Childrens Hosp, Brisbane, Qld, Australia

[9] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9PL, Lancs, England

[10] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[11] Great North Childrens Hosp, Newcastle Upon Tyne, Tyne & Wear, England

[12] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Ctr Human Immunobiol, Houston, TX 77030 USA

[13] Baylor Coll Med, Dept Pediat, Div Immunol Allergy & Rheumatol, Houston, TX 77030 USA

[14] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[15] Texas Childrens Hosp, Houston, TX 77030 USA

[16] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[17] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[18] Univ Paris 05, Lab Human Genet Infect Dis, Necker Branch, INSERM,U1163,Inst IMAGINE,Necker Med Sch, Paris, France

[19] Necker Hosp Sick Children, AP HP, Pediat Hematol & Immunol Unit, Paris, France

[20] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA

[21] Howard Hughes Med Inst, New York, NY USA

[22] Natl Inst Pediat, Immunodeficiencies Res Unit, Mexico City, DF, Mexico

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

DOI  :  10.1016/j.jaci.2016.07.016

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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