Dedicator of cytokinesis 8–deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells - 19/04/17
, Bethany Pillay, BSc Hons a, b, Katrina L. Randall, MBBS, PhD, FRACP, FRCPA c, d, Danielle T. Avery, BApplSci a, Tri Giang Phan, MBBS, PhD, FRACP, FRCPA a, b, Paul Gray, FRACP e, John B. Ziegler, MD, FRACP e, Joanne M. Smart, MBBS, FRACP f, Jane Peake, MBBS g, Peter D. Arkwright, FRCPCH, DPhil h, Sophie Hambleton, DPhil i, Jordan Orange, MD, PhD j, Christopher C. Goodnow, PhD a, b, Gulbu Uzel, MD k, Jean-Laurent Casanova, MD, PhD l, m, n, o, Saul Oswaldo Lugo Reyes, MD p, Alexandra F. Freeman, MD k, Helen C. Su, MD, PhD q, Cindy S. Ma, PhD a, b, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Key words : Dedicator of cytokinesis 8, CD4+ T-cell differentiation, TH2 skewing, allergy, atopic disease, chronic mucocutaneous candidiasis, viral immunity
Abbreviations used : APC, AR-HIES, CFSE, CMC, DOCK8, HPV, HSV, ICOS, NK, PD-1, PE, PID, PMA, RORC, STAT, TAE, T-bet, TCM, TCR, TEM, TFH, Treg
Plan
| Supported by research grants awarded by the National Health and Medical Research Council (NHMRC) of Australia (to C.S.M. and S.G.T.: 1060303, 596813, and 1016953; to K.L.R.: 1022922), and Rockefeller University Center for Clinical and Translational Science (5UL1RR024143 to J.-L.C.). This research was supported in part by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. C.S.M. is a recipient of a Career Development Fellowship (1008820), and S.G.T. is a Principal Research Fellowship (1042925) from the NHMRC of Australia and a Fulbright Senior Scholar. |
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| Disclosure of potential conflict of interest: S. G. Tangye receives grant support from the National Health & Medical Research Council of Australia and travel support from ESID and the Jeffery Modell Foundation. B. Pillay receives grant support from UNSW and travel support from FIMSA. K. L. Randall receives grant support from NHMRC Australia. J. B. Ziegler receives travel support from the Modell Foundation. J. Orange serves on the board of ADMA Biologics; serves as a consultant for CSL Behring, Grifols, Baxalta, and Walgreens; receives payments for lectures from Baxalta; has a patent with Children's Hospital of Philadelphia; and royalties from UpToDate. C. C. Goodnow receives grant support from the National Institutes of Health, serves as a consultant for Ideaya, and provided expert testimony for FB Rice. J.-L. Casanova serves on the board for the ADMA Scientific Advisory Board; serves as a consultant for Regeneron, Bioaster, Pfizer, Novartis, Sanofi, and Genentech; and receives grant support from Merck Sharpe & Dohme, Biogen Idec, and Pfizer. C. S. Ma receives grant funding from the National Health & Medical Research Council of Australia and receives payments for lectures from Baxalta. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 3
P. 933-949 - mars 2017 Retour au numéro
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