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*

*Corresponding author for this work
14 Citations (Scopus)


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.

Original languageEnglish
JournalJournal of Steroid Biochemistry and Molecular Biology
Pages (from-to)1-9
Number of pages9
Publication statusPublished - 05.2019

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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