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Vitamin D (1,25(OH
Authors
Abbate
Aggarwal
+53 more
Barbey-Morel
Baruah
Bergin
Bibek Gooptu
Bornhorst
Catherine M. Hawrylowicz
Charlotte Cheadle
Christakos
Claudia Kemper
Daha
Dankers
David F. Richards
de Serres
Demeo
Dierich
Dimeloe
Eden
Freeley
Frenzel
Ghannam
Gottlieb
Gramegna
Greene
Gupta
Hammerberg
Hebe Chen
James M. McDonnell
Janciauskiene
Jeffery
John Raynes
Kemper
Kildsgaard
Lewis
Lewis
Lewis
Lomas
Lomas
Louise V. Rice
Magenau
Mann
Marciniak
Mueller
Mun Peak Nyon
Parfrey
Paul Lavender
Paul Pfeffer
Pfeffer
Sarah Dimeloe
Urry
Urry
Vanherwegen
Vignesh
Xystrakis
Publication date
25 January 2019
Publisher
'Elsevier BV'
Doi
Cite
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.
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