Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired Laurence Pellerin, PhD, Jennifer Anne Jenks,

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Presentation transcript:

Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired Laurence Pellerin, PhD, Jennifer Anne Jenks, BS, Sharon Chinthrajah, MD, Tina Dominguez, PA-C, MMS, Whitney Block, NP, Xiaoying Zhou, PhD, Arram Noshirvan, BS, Silvia Gregori, PhD, Maria Grazia Roncarolo, MD, Kari Christine Nadeau, MD, PhD, Rosa Bacchetta, MD Journal of Allergy and Clinical Immunology Volume 141, Issue 1, Pages 202-213.e8 (January 2018) DOI: 10.1016/j.jaci.2017.05.045 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 202-213 Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Pea-mDCs and pea–DC-10s from HC subjects and patients with PA present a mature phenotype. Expression levels of CD11c, CD14, and CD86 in mDCs and DC-10s of HC subjects and patients with PA are shown. Representative data from 1 HC subject of 7 (upper panel) and 1 patient with PA of 21 (lower panel) were used. Red = mDCs, unstained; blue = mDCs; green = DC-10s, unstained; orange = DC-10s. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TR1 cells are induced at similar frequencies from HC subjects and patients with PA. Frequencies of CD4+CD45RA−CD49b+LAG3+ TR1 cells in pea-Tm and pea-T10 cells of HC subjects (Fig 2, A, B, and D) and patients with PA (Fig 2, A and C-E) are shown. A, Dot plots for a representative HC of 7 (upper panel) and patient with PA of 21 (lower panel). B and C, Cumulative data of LAG3 and CD49b expression are represented for HC subjects (Fig 2, B) and patients with PA (Fig 2, C). D, Comparison of the percentages of CD49b+LAG3+ cells in pea-T10 cells of HC subjects and patients with PA. E, Comparison of the percentages of CD49b+LAG3+ cells in pea-T10 cells of all 3 cohorts of patients with PA. Bas, Baseline. Mean values and SDs are shown. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Pea–DC-10s induce antigen-specific CD4+ T-cell anergy in all HC subjects but only in a minority of patients with PA. Proliferation of pea-Tm and pea-T10 cell lines stimulated with autologous Ara h 1/2 (pea)–mDCs for 5 days for HC subjects and patients with PA is shown. A, Dot plot for a representative HC subject (left panel) and 2 representative patients with PA (PA-1 presenting anergy and PA-2 not presenting anergy; middle and right panels, respectively). B, Proliferative responses of pea-Tm (black columns) and pea-T10 (gray columns) cells are shown. Percentage of anergy (calculated as percentage of proliferating [pea-Tm cells − pea-T10 cells]/pea-Tm cells) is indicated for each experiment. ni, Anergy not induced. C and D, Cumulative data for HC subjects (n = 7) and patients with PA (n = 21; Fig 3, C) and comparison of PA cohorts (Fig 3, D). Bas, Baseline. Each symbol represents a single experiment. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Pea-T10 cells of HC subjects but not patients with PA produce fewer TH2 cytokines than pea-Tm cells. Detection of cytokines by ELISA (in picograms per milliliter) in supernatants of pea-Tm and pea-T10 cells of HC subjects and patients with PA restimulated with pea-mDCs for 48 hours is shown. Results are shown for IL-4 (A) and IL-5 (B) in HC subjects (left panels) and patients with PA (middle panels), with each symbol representing a single experiment. Right panels represent a comparison of all HC subjects and patients with PA; mean cytokine detection levels are shown. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Peanut-specific T cells are more abundant in TR1 cells compared with the total memory CD4+ population of pea-T10 cells in patients with PA. Expression of CD69 and CD137 after restimulation with pea-mDCs was assessed for pea-T10 cells of patients with PA. A and B, Dot plot for a representative donor shows expression of CD69 (Fig 5, A) and CD137 (Fig 5, B) in the CD45RA− and CD49b+LAG3+ populations for unstimulated cells (upper panels) or cells stimulated with pea-mDCs (lower panels). C and D, Percentage of CD4+ T cells specifically upregulating CD69 (n = 14; Fig 5, C) and CD137 (n = 12; Fig 5, D) upon activation (subtracting the background from the unstimulated cells) is represented for each donor within the CD45RA− and CD49b+LAG3+ populations. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Expression of gut-homing molecules is higher in TR1 cells than in the total memory CD4+ population of pea-T10 cells. Expression of the gut-homing molecules GPR15 (A) and CCR9 (B) in CD49b+LAG3+ TR1 and total memory cell populations of pea-T10 cells of HC subjects and patients with PA is shown. Cumulative data are represented for Fig 6, A for HC (n = 5) and PA patients (n = 19) and Fig 6, B and for HC (n = 2) and PA patients (n = 13). SSC, Side scatter. Green = HC subjects; red = patients with PA. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Scheme of induction of mDCs, DC-10s, peanut-specific T-cell lines, and readouts. A, Dendritic cell and T-cell line induction. B, Readouts for T-cell lines. CFSE, Carboxyfluorescein succinimidyl ester. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 mDCs and DC-10s from HC subjects and patients with PA present a mature phenotype. Comparison of the percentage of CD11c+ (A), CD14+ (B), and CD86+ (C) cells in mDCs and DC-10s of HC subjects (n = 7) and all 3 cohorts of patients with PA (n = 21) are shown (Bas, n = 7; ST-OIT, n = 7; LT-OIT, n = 7). Bas, Baseline. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Pea-Tm and pea-T10 cells of HC subjects and patients with PA present a partially activated phenotype. The frequency of CD4+CD45RA−CD25+ cells in pea-Tm and pea-T10 cells of HC subjects and patients with PA is shown. A, Dot plot for a representative HC subject (of 7 tested; upper panel) and patient with PA (of 21 tested; lower panel) show expression of CD25 in pea-Tm cells (left panel) and pea-T10 cells (right panel). SSC, Side scatter. B and C, Histogram representing cumulative data of CD25 expression for HC subjects and patients with PA (Fig E3, B) and comparison of PA cohorts (ST-OIT, n = 7; LT-OIT, n = 7; Fig E3, C). Bas, Baseline. Means and SDs are shown. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Pea–DC-10s induce antigen-specific CD4+ T-cell anergy in all HC subjects but only in a minority of patients with PA. Proliferation of pea-Tm and pea-T10 cell lines stimulated with autologous Ara h 1/2 (pea)−mDCs for 4 days or TT-mDCs for 5 days for HC subjects and patients with PA are shown. Bas, Baseline. A, Proliferative responses of pea-Tm cells (black columns) and pea-T10 cells (gray columns) in response to Ara h 1/2. B and C, Cumulative data for HC subjects and patients with PA (Fig E4, B) and comparison of PA cohorts (Fig E4, C). Each symbol represents a single experiment. D, Dot plots of proliferation in response to TT restimulation are shown for representative HC subjects (left panel) and patients with PA. E, Proliferative responses of pea-Tm cells (black columns) and pea-T10 cells (gray columns) to TT are shown. Percentage of anergy (calculated as percentage of proliferating [pea-Tm cells − pea-T10 cells]/pea-Tm cells) is indicated for each experiment. ni, Anergy not induced. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 IL-10 and IFN-γ levels are comparable in pea-Tm and pea-T10 cells of HC subjects and patients with PA, and IL-4 and IL-5 levels in pea-T10 cells are negatively correlated with the percentage of anergy. Results of detection of cytokines by means of ELISA (in picograms per milliliter) in supernatants of pea-Tm and pea-T10 cells of HC subjects and patients with PA restimulated with pea-mDC cells for 48 hours are shown. A and B, Results are shown for IL-10 (Fig E5, A) and IFN-γ (Fig E5, B) of HC subjects (left panels) and patients with PA (middle panels). Each symbol represents a single experiment. Right panels represent a comparison of all HC subjects and patients with PA; mean cytokine detection levels are shown. C-E, Scatter plots comparing levels of IL-4 (in picograms per milliliter; Fig E5, C), IL-5 (in picograms per milliliter; Fig E5, D), and IL-10 (in picograms per milliliter; Fig E5, E) detected in pea-T10 cell cultures restimulated with pea-mDCs for 48 hours and the percentage of anergy (calculated as percentage of proliferating [pea-Tm cells − pea-T10 cells]/pea-Tm cells after restimulation with pea-mDCs for 5 days). The trendline is shown, and the correlation coefficient and statistical significance are indicated. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 TT-specific T cells are present at the same frequencies in TR1 cells compared with the total memory CD4+ population of pea-T10 cells in patients with PA. Expression of CD69 and CD137 after restimulation with TT-mDCs was assessed for pea-T10 cells of patients with PA. A and B, Dot plot for a representative donor shows CD69 (Fig E6, A) and CD137 (Fig E6, B) expression in the CD45RA− and CD49b+LAG3+ populations for cells unstimulated (upper panels) or stimulated with TT-mDC (lower panels). C and D, Percentage of CD4+ T cells specifically upregulating CD69 (n = 13; Fig E6, C) and CD137 (n = 9; Fig E6, D) on activation (subtracting the background from the unstimulated cells) is represented for each donor within the CD45RA− and CD49b+LAG3+ populations. Journal of Allergy and Clinical Immunology 2018 141, 202-213.e8DOI: (10.1016/j.jaci.2017.05.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions