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, PhD, Bethany.

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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, PhD, Bethany Pillay, BSc Hons, Katrina L. Randall, MBBS, PhD, FRACP, FRCPA, Danielle T. Avery, BApplSci, Tri Giang Phan, MBBS, PhD, FRACP, FRCPA, Paul Gray, FRACP, John B. Ziegler, MD, FRACP, Joanne M. Smart, MBBS, FRACP, Jane Peake, MBBS, Peter D. Arkwright, FRCPCH, DPhil, Sophie Hambleton, DPhil, Jordan Orange, MD, PhD, Christopher C. Goodnow, PhD, Gulbu Uzel, MD, Jean-Laurent Casanova, MD, PhD, Saul Oswaldo Lugo Reyes, MD, Alexandra F. Freeman, MD, Helen C. Su, MD, PhD, Cindy S. Ma, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 3, Pages 933-949 (March 2017) DOI: 10.1016/j.jaci.2016.07.016 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Phenotype of the peripheral CD4+ T-cell compartment in DOCK8-deficient patients. A, Frequency of CD4+ T cells in healthy donors and DOCK8-deficient patients. B and C, Naive (CD45RA+CCR7+), TCM (CD45RA−CCR7+), and TEM (CD45RA−CCR7−) cell populations in healthy donors (solid symbols; n = 25) and DOCK8-deficient patients (open symbols; n = 18) were enumerated based on expression of CD45RA and CCR7. D-G, PBMCs were labeled with mAbs against CD4, CD45RA, CD25, CD127, CXCR5, CXCR3, and CCR6. Fig 1, D, Treg cells were identified as CD25hiCD127lo. Fig 1, E, Among the non-Treg cell population, naive and TFH cells were identified as CXCR5−CD45RA+ and CXCR5+CD45RA−, respectively. Fig 1, F, TH1, TH2, and TH17 populations were identified within the population of CXCR5−CD45RA− memory CD4+ T cells as CXCR3+CCR6−, CCR6−CXCR3−, and CCR6+CXCR3− cells, respectively. Fig 1, G, By using this gating, the frequency of Treg, TFH, TH1, TH2, and TH17 cells within the CD4+ T-cell compartment was determined in healthy subjects (solid symbols; n = 15 or 16) and in DOCK8-deficient patients (open symbols; n = 10 or 11). Each point represents an individual donor or patient. Statistics were performed with Prism software by using the Student t test. H-M, Naive (CD45RA+CCR7+), TCM (CD45RA−CCR7+), and TEM (CD45RA−CCR7−) cell populations in healthy donors (solid symbols) and DOCK8-deficient patients (open symbols) were identified and assessed for expression of CD27 (Fig 1, H), CD28 (Fig 1, I), CD127 (Fig 1, J), CD57 (Fig 1, K), CD95 (Fig 1, L), and PD-1 (Fig 1, M). Each point corresponds to the mean ± SEM percentage of cells expressing the indicated surface receptor or the mean fluorescence intensity (MFI) of expression (n = 4-12 healthy donors or DOCK8-deficient patients). Statistics were performed with Prism software by using the t test. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 933-949DOI: (10.1016/j.jaci.2016.07.016) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 DOCK8-deficient memory CD4+ T cells display a TH2 cytokine expression bias. Naive (CD45RA+CCR7+) and memory (CD45RA−CCR7+/−) CD4+ T cells were isolated from healthy donors and DOCK8-deficient patients and cultured with TAE beads for 5 days. Cells were then restimulated with PMA/ionomycin for 6 hours in the presence of Brefeldin A for the last 4 hours. Intracellular expression of IL-2 (A), TNF-α (B), IL-4 (C), IFN-γ (D), IL-17A (E), IL-22 (F), IL-21 (G), and IL-10 (H) was determined by using saponin as the permeabilizing agent, followed by flow cytometric analysis. Data represent means ± SEMs of 8 healthy donors or 8 DOCK8-deficient patients. Statistics were performed with Prism software by using 1-way ANOVA. *P < .05, **P < .01, ***P < .005, and ****P < .001. Journal of Allergy and Clinical Immunology 2017 139, 933-949DOI: (10.1016/j.jaci.2016.07.016) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 DOCK8-deficient memory CD4+ T cells secrete increased quantities of the TH2 cytokines IL-4, IL-5, and IL-13 independently of differences in cell proliferation. Naive and memory CD4+ T cells were sorted from healthy donors and DOCK8-deficient patients and cultured with TAE beads for 5 days. A-J, After this time, culture supernatants were examined for secretion of IL-4 (Fig 3, A), IL-5 (Fig 3, B), IL-13 (Fig 3, C), IFN-γ (Fig 3, D), TNF (Fig 3, E), IL-17A (Fig 3, F), IL-17F (Fig 3, G), IL-6 (Fig 3, H), IL-10 (Fig 3, I), and IL-2 (Fig 3, J) by using a custom-designed cytometric bead array (BD Biosciences). Data represent means ± SEMs of experiments by using cells from 9 healthy donors or DOCK8-deficient patients. Statistics were performed with Prism software by using 1-way ANOVA. K and L, Naive (Fig 3, K) and memory (Fig 3, L) CD4+ T cells were isolated from healthy donors (n = 4) and DOCK8-deficient patients (n = 4), labeled with CFSE, and cultured with TAE beads for 5 days. After this time, the frequency of cells in each division was determined by means of dilution of CFSE. M, Sorted naive and memory CD4+ cells were immediately restimulated with PMA/ionomycin for 6 hours in the presence of Brefeldin A and IL-4 expression determined by using intracellular staining and flow cytometry. N and O, Naive and memory CD4+ T cells were labeled with CFSE and cultured with TAE beads for 5 days, and the proportion of cells expressing IFN-γ (Fig 3, L) or IL-4 (Fig 3, M) in each division interval was determined by means of dilution of CFSE. Data represent means ± SEMs of 2 to 4 healthy donors and DOCK8-deficient patients. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 933-949DOI: (10.1016/j.jaci.2016.07.016) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Intrinsic defects in CD4+ T-cell cytokine secretion caused by DOCK8 mutations. A and B, Naive (Fig 4, A) and memory (Fig 4, B) CD4+ T cells were isolated from healthy donors and DOCK8-deficient patients and activated under neutral conditions (TH0; TAE only), or TH1-polarizing (+IL-12), TH2-polarizing (+IL-4), or TH17-polarizing (+IL-1β, IL-6, IL-21, IL-23, TGF-β, and prostaglandin) conditions. After 5 days, secretion of TH1 (IFN-γ), TH2 (IL-5 and IL-13), and TH17 (IL-17A and IL-17F) cytokines was determined by using the cytometric bead array. Data represent means ± SEMs of experiments with cells from 12 healthy donors and 8 DOCK8-deficient patients. C and D, Expression of T-bet (Fig 4, C) and GATA-3 (Fig 4, D) was determined by means of flow cytometry; data represent the fold change (mean ± SEM) in expression of the indicated transcription factor relative to TH0 culture of the healthy control subject. E, expression of RORC was determined by using quantitative PCR. Data represent means and SEMs of 2 to 3 healthy donors and DOCK8-deficient patients. F, Memory CD4+ T cells from healthy donors or DOCK8-deficient patients (n = 2) were cultured with TAE beads at a cell/bead ratio of 2:1 and 0.5:1, and expression of ICOS, CD25, CD69, and CD95 was determined before culture (day 0) and 3 days after activation. Values represent means ± SEMs of the mean fluorescence intensity (MFI) of each of the indicated surface receptors. Statistics were performed with Prism software by using 2-way ANOVA. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 933-949DOI: (10.1016/j.jaci.2016.07.016) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IgE in DOCK8-deficient patients is specific for staple foods but not other antigens, such as house dust mites. Plasma from healthy donors and DOCK8-deficient patients was analyzed for IgE specific for a staple food mix (egg white, milk, codfish, wheat, peanut, and soybean; A) and a house dust mite mix (B) by using ImmunoCAP. Data represent means ± SEMs of 13 healthy donors and 15 DOCK8-deficient patients. The dotted line refers to the upper limit of the negative reference interval (0.35 kUA/L). *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 933-949DOI: (10.1016/j.jaci.2016.07.016) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions