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

• Published in: The Journal of steroid biochemistry and molecular biology 2019-05, Vol.189, p.1
• Main Authors: Dimeloe, Sarah, Rice, Louise V, Chen, Hebe, Cheadle, Charlotte, Raynes, John, Pfeffer, Paul, Lavender, Paul, Richards, David F, Nyon, Mun Peak, McDonnell, James M, Kemper, Claudia, Gooptu, Bibek, Hawrylowicz, Catherine M
• Format: Article
• Language: English
• Subjects: alpha 1-Antitrypsin - immunology; Calcitriol - pharmacology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Humans; Immunologic Factors - pharmacology; Interleukin-10 - immunology; Vitamins - pharmacology
• ISSN: 1879-1220
• DOI: 10.1016/j.jsbmb.2019.01.014

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.