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Human TH17 cell development requires processing of dendritic cell–derived CXCL8 by neutrophil elastase  Yuri Souwer, PhD, Tom Groot Kormelink, PhD, Esther.

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Presentation on theme: "Human TH17 cell development requires processing of dendritic cell–derived CXCL8 by neutrophil elastase  Yuri Souwer, PhD, Tom Groot Kormelink, PhD, Esther."— Presentation transcript:

1 Human TH17 cell development requires processing of dendritic cell–derived CXCL8 by neutrophil elastase  Yuri Souwer, PhD, Tom Groot Kormelink, PhD, Esther W. Taanman-Kueter, BSc, Femke J. Muller, BSc, Toni M.M. van Capel, BSc, Domonkos V. Varga, MSc, Yotam E. Bar-Ephraim, PhD, Marcel B.M. Teunissen, PhD, S. Marieke van Ham, PhD, Taco W. Kuijpers, MD, PhD, Diana Wouters, PhD, Linde Meyaard, PhD, Esther C. de Jong, PhD  Journal of Allergy and Clinical Immunology  Volume 141, Issue 6, Pages e5 (June 2018) DOI: /j.jaci Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Neutrophils are essential for the induction of human TH17 cells. A, Percentage of C albicans–specific memory TH17 cells analyzed after coculture with C albicans–activated DCs. Cells were isolated from 4 patients with different functional neutrophil defects. B and C, Highly pure human CD4+CD45RA+CD45RO− naive T cells were cocultured with C albicans–activated DCs with or without neutrophils and restimulated after a resting phase. Shown are pooled data of the percentage IL-17–expressing cells (healthy donors, Fig 1, B), and RORC2 and IL-17A mRNA expression in antigen-specific T cells sorted on day 13 (Fig 1, C, n = 9, mean ± SEM). D, T-cell proliferation (measured by CFSE dilution) in different culture conditions. a.u., Arbitrary units; CFSE, carboxyfluorescein succinimidyl ester; Tn, naive T cell; Tmem, memory T cell. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 NE processes CXCL-8(77) into CXCL-8(72), which is necessary for human TH17 cell development. TH17 cell development from highly purified human CD4+CD45RA+CD45RO− naive T cells upon coculture with C albicans–activated DCs with or without neutrophils (healthy donor vs FHL-5 patient) (A), or with supernatant from fMLP-activated neutrophils (B), or in the presence of SIRL-1–activating antibodies (C), Sivelestat, a selective NE inhibitor (D), NE (E), recombinant CXCL-8(77) or CXCL-8(72) (G), or reparixin, a specific inhibitor of CXCR1 and CXCR2 (H) (all n = 3, mean ± SEM). F, A representative silverstain of CXCL-8 immunoprecipitated from culture supernatants of indicated cocultures. I, TH17 cell development from CD4+CXCR1+ T cells sorted 4 days after activation with C albicans–activated DCs in the presence or absence of neutrophils (n = 5, mean ± SEM). J, TH17 cell development from naive CD4+ T cells after activation with C albicans–activated DCs in the presence of different ratios of CXCL-8(72) and CXCL-8(77) (n = 3, mean ± SEM). aSIRL, Anti-SIRL-1; fMLP, N-formyl-methionyl-leucyl-phenylalanine; Rel. % IL-17+ cells, relative expression of IL-17+ cells in specific conditions normalized to conditions with neutrophils; SIRL-1, signal inhibitory receptor on leukocytes-1; Tn, naive T cell; Tmem, memory T cell. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E1 Neutrophils are required for human TH17 cell development from naive T cells. A, Purity of isolated neutrophils (n = 6, mean ± SEM). B-E, Naive T cells were primed by C albicans–activated DCs in the absence or presence of neutrophils and restimulated after a resting phase. Shown are IL-17 release (Fig E1, B, n = 7, mean ± SEM), TBX21 (encoding T-bet) mRNA expression in antigen-specific T cells sorted on day 13 (Fig E1, C, n = 9, mean ± SEM), percentage of IFN-γ-producing T cells (Fig E1, D), and IFN-γ release (Fig E1, E, n = 6, mean ± SEM). F, The presence of neutrophils did not potentiate or inhibit the proliferation (measured by CFSE dilution) of T cells. G, DC-mediated activation of TH17 cells from C albicans–specific memory T cells in the absence or presence of neutrophils (n = 6, mean ± SEM). H and I, Influence of the presence of memory and recently activated T cells on the percentage of TH17 cells upon restimulation (n = 4, mean ± SEM). In Fig E1, H, Tn cells and/or Tmem cells were stimulated by C albicans–activated DCs. In Fig E1, I, T cells were stimulated with anti-CD3/anti-CD28–coated beads in the presence of IL-1β and IL-6, combined with neutralizing anti–IFN-γ and anti–IL-4.E5 CFSE, Carboxyfluorescein succinimidyl ester; Tn, naive T cell; Tmem, memory T cell. *P < .05. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E2 The critical role for neutrophils in TH17 cell development is independent of DC subset and is not restricted to C albicans. A, TH17 cell induction from purified human CD4+CD45RA+CD45RO− naive T cells by human skin–derived Langerhans cells (LCs) and dermal DCs (DDCs) in the presence or absence of neutrophils (n = 3, mean ± SEM). B, DC-mediated induction of yeast and bacteria-specific TH17 cells from naive T cells (n = 3, mean ± SEM). *P < .05. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E3 Essential roles for NE and CXCL8 in inducing TH17 cell formation. A, NE concentrations in culture supernatants collected 24 hours after activation with C albicans of indicated cocultures (n = 5, mean ± SEM). B, Production of IL-8 by C albicans–activated neutrophils, DCs, and cocultures of both (n = 3, mean ± SEM). C, Gating strategy for sorting CXCR1+ T cells 4 days after starting a coculture of C albicans–activated DCs and naive T cells, with or without neutrophils. D, TH17 cell development from CXCR1− and CXCR1+ T cells sorted as indicated in Fig E3, C, both derived from cocultures containing neutrophils (n = 5, mean ± SEM). Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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