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    Vitamin D (1,25(OH

    Dimeloe, S. and Rice, L.V. and Chen, H. and Cheadle, C. and Raynes, J. and Pfeffer, P. and Lavender, P. and Richards, D.F. and Nyon, Mun and McDonnell, J.M. and Kemper, C. and Gooptu, Bibekbrata and Hawrylowicz, C. (2019) Vitamin D (1,25(OH. The Journal of Steroid Biochemistry and Molecular Biology 189 , pp. 1-9. ISSN 1879-1220.

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    Abstract

    Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) D3) in human CD4 T cells revealed that 1,25(OH) 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) 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) 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) 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) D3-induced IL-10 expression in CD4 T cells, interacting with C3a to drive IL-10 expression. [Abstract copyright: Copyright © 2019. Published by Elsevier Ltd.]

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): C3a, Complement, IL-10, Immune regulation, α-1-Antitrypsin
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    SWORD Depositor: Mr Joe Tenant
    Depositing User: Mr Joe Tenant
    Date Deposited: 05 Mar 2019 10:01
    Last Modified: 28 Jul 2019 07:17
    URI: http://eprints.bbk.ac.uk/id/eprint/26210

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