Vitamin D (1,25(OH)                         2                         D3) induces α-1-antitrypsin synthesis by CD4                         +                          T cells, which is required for 1,25(OH)                         2                         D3-driven IL-10

Sarah Dimeloe; Louise V. Rice; Hebe Chen; Charlotte Cheadle; John Raynes; Paul Pfeffer; Paul Lavender; David F. Richards; Mun Peak Nyon; James M. McDonnell; Claudia Kemper; Bibek Gooptu; Catherine M. Hawrylowicz

doi:10.1016/j.jsbmb.2019.01.014

Vitamin D (1,25(OH) ₂ D3) induces α-1-antitrypsin synthesis by CD4 ⁺ T cells, which is required for 1,25(OH) ₂ D3-driven IL-10

Sarah Dimeloe, Louise V. Rice, Hebe Chen, Charlotte Cheadle, John Raynes, Paul Pfeffer, Paul Lavender, David F. Richards, Mun Peak Nyon, James M. McDonnell, Claudia Kemper, Bibek Gooptu, Catherine M. Hawrylowicz^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Systemische Entzündungsforschung

30 Zitate (Scopus)

Abstract

Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) ₂ D3) in human CD4 ⁺ T cells revealed that 1,25(OH) ₂ D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) ₂ D3-treated CD4 ⁺ T cells, but not in CD8 ⁺ T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4 ⁺ T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4 ⁺ T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 ⁺ T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) ₂ D3-driven CD4 ⁺ T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH) ₂ D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4 ⁺ T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH) ₂ D3-induced IL-10 expression in CD4 ⁺ T cells, interacting with C3a to drive IL-10 expression.

Originalsprache	Englisch
Zeitschrift	Journal of Steroid Biochemistry and Molecular Biology
Jahrgang	189
Seiten (von - bis)	1-9
Seitenumfang	9
ISSN	0960-0760
DOIs	https://doi.org/10.1016/j.jsbmb.2019.01.014
Publikationsstatus	Veröffentlicht - 05.2019

Fördermittel

SD and LR were recipients of Medical Research Council (MRC) funded PhD Studentships through the MRC & Asthma UK Centre for Allergic Mechanisms of Asthma . CK was supported by an MRC Research Grant (Grant no. G1002165 ) and the Medical Research Council Centre for Transplantation , KCL. CH with LR, HC and CC, as well as MPN were supported by grants from the Alpha-1 Foundation . CMH, CK and PEP are supported by the Department of Health, National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. We gratefully acknowledge the work undertaken to provide reagents by Marie Pang (KCL, London), Doris Quay (Birkbeck College, London) and Professor Joerg Koehl (Lubeck University, Germany) and the assistance of Professor David Lomas (UCL) and the Cambridge Institute of Medical Research (CIMR, University of Cambridge) for use of laboratory facilities. Microscale thermophoresis assays were conducted with the kind assistance of Dr Tina Daviter (ISMB Biophysics facility), Dr Mark Pfuhl (Randall Division, KCL) and Dr James Wilkinson (Nanotemper Technologies). We acknowledge support from our research nurse, Kheem Jones.

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SDG 3 – Gesundheit und Wohlergehen

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Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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10.1016/j.jsbmb.2019.01.014

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Dimeloe, S., Rice, L. V., Chen, H., Cheadle, C., Raynes, J., Pfeffer, P., Lavender, P., Richards, D. F., Nyon, M. P., McDonnell, J. M., Kemper, C., Gooptu, B., & Hawrylowicz, C. M. (2019). Vitamin D (1,25(OH) ₂ D3) induces α-1-antitrypsin synthesis by CD4 ⁺ T cells, which is required for 1,25(OH) ₂ D3-driven IL-10. Journal of Steroid Biochemistry and Molecular Biology, 189, 1-9. https://doi.org/10.1016/j.jsbmb.2019.01.014

Dimeloe, Sarah ; Rice, Louise V. ; Chen, Hebe et al. / Vitamin D (1,25(OH) ₂ D3) induces α-1-antitrypsin synthesis by CD4 ⁺ T cells, which is required for 1,25(OH) ₂ D3-driven IL-10. in: Journal of Steroid Biochemistry and Molecular Biology. 2019 ; Jahrgang 189. S. 1-9.

@article{e071fc1a53224f13ac8843912ffc226b,

title = "Vitamin D (1,25(OH) 2 D3) induces α-1-antitrypsin synthesis by CD4 + T cells, which is required for 1,25(OH) 2 D3-driven IL-10",

abstract = " Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) 2 D3) in human CD4 + T cells revealed that 1,25(OH) 2 D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) 2 D3-treated CD4 + T cells, but not in CD8 + T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4 + T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4 + T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 + T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) 2 D3-driven CD4 + T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH) 2 D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4 + T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH) 2 D3-induced IL-10 expression in CD4 + T cells, interacting with C3a to drive IL-10 expression. ",

author = "Sarah Dimeloe and Rice, \{Louise V.\} and Hebe Chen and Charlotte Cheadle and John Raynes and Paul Pfeffer and Paul Lavender and Richards, \{David F.\} and Nyon, \{Mun Peak\} and McDonnell, \{James M.\} and Claudia Kemper and Bibek Gooptu and Hawrylowicz, \{Catherine M.\}",

note = "Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = may,

doi = "10.1016/j.jsbmb.2019.01.014",

language = "English",

volume = "189",

pages = "1--9",

journal = "Journal of Steroid Biochemistry and Molecular Biology",

issn = "0960-0760",

publisher = "Elsevier Ltd",

}

Dimeloe, S, Rice, LV, Chen, H, Cheadle, C, Raynes, J, Pfeffer, P, Lavender, P, Richards, DF, Nyon, MP, McDonnell, JM, Kemper, C, Gooptu, B & Hawrylowicz, CM 2019, 'Vitamin D (1,25(OH) ₂ D3) induces α-1-antitrypsin synthesis by CD4 ⁺ T cells, which is required for 1,25(OH) ₂ D3-driven IL-10', Journal of Steroid Biochemistry and Molecular Biology, Jg. 189, S. 1-9. https://doi.org/10.1016/j.jsbmb.2019.01.014

Vitamin D (1,25(OH) ₂ D3) induces α-1-antitrypsin synthesis by CD4 ⁺ T cells, which is required for 1,25(OH) ₂ D3-driven IL-10. / Dimeloe, Sarah; Rice, Louise V.; Chen, Hebe et al.
in: Journal of Steroid Biochemistry and Molecular Biology, Jahrgang 189, 05.2019, S. 1-9.

Publikation: Beiträge in Fachzeitschriften › Zeitschriftenaufsätze › Forschung › Begutachtung

TY - JOUR

T1 - Vitamin D (1,25(OH) 2 D3) induces α-1-antitrypsin synthesis by CD4 + T cells, which is required for 1,25(OH) 2 D3-driven IL-10

AU - Dimeloe, Sarah

AU - Rice, Louise V.

AU - Chen, Hebe

AU - Cheadle, Charlotte

AU - Raynes, John

AU - Pfeffer, Paul

AU - Lavender, Paul

AU - Richards, David F.

AU - Nyon, Mun Peak

AU - McDonnell, James M.

AU - Kemper, Claudia

AU - Gooptu, Bibek

AU - Hawrylowicz, Catherine M.

PY - 2019/5

Y1 - 2019/5

N2 - Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) 2 D3) in human CD4 + T cells revealed that 1,25(OH) 2 D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) 2 D3-treated CD4 + T cells, but not in CD8 + T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4 + T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4 + T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 + T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) 2 D3-driven CD4 + T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH) 2 D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4 + T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH) 2 D3-induced IL-10 expression in CD4 + T cells, interacting with C3a to drive IL-10 expression.

AB - Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) 2 D3) in human CD4 + T cells revealed that 1,25(OH) 2 D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) 2 D3-treated CD4 + T cells, but not in CD8 + T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4 + T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4 + T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 + T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) 2 D3-driven CD4 + T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH) 2 D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4 + T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH) 2 D3-induced IL-10 expression in CD4 + T cells, interacting with C3a to drive IL-10 expression.

UR - https://www.scopus.com/pages/publications/85061024390

U2 - 10.1016/j.jsbmb.2019.01.014

DO - 10.1016/j.jsbmb.2019.01.014

M3 - Journal articles

C2 - 30690074

AN - SCOPUS:85061024390

SN - 0960-0760

VL - 189

SP - 1

EP - 9

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

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Dimeloe S, Rice LV, Chen H, Cheadle C, Raynes J, Pfeffer P et al. Vitamin D (1,25(OH) ₂ D3) induces α-1-antitrypsin synthesis by CD4 ⁺ T cells, which is required for 1,25(OH) ₂ D3-driven IL-10. Journal of Steroid Biochemistry and Molecular Biology. 2019 Mai;189:1-9. doi: 10.1016/j.jsbmb.2019.01.014

Vitamin D (1,25(OH) 2 D3) induces α-1-antitrypsin synthesis by CD4 + T cells, which is required for 1,25(OH) 2 D3-driven IL-10