Abstract
Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH)2D3) in human CD4+ T cells revealed that 1,25(OH)2D3 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)2D3-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)2D3-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)2D3. 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)2D3-induced IL-10 expression in CD4+ T cells, interacting with C3a to drive IL-10 expression.
Highlights
Vitamin D is a potent anti-inflammatory mediator, with its active form (1,25-dihydroxyvitamin D, 1,25(OH)2D3) having a range of immune-regulatory functions including direct induction of anti-microbial functions and the generation of tolerogenic antigen presenting cells and regulatory T cells [1]
This study identifies a novel interaction in the human immune system, between two ubiquitous mediators, α-1-antitrypsin and C3a, which directly bind to each other, and at physiological concentrations interact to drive anti-inflammatory IL-10 expression by CD4+ T cells
Beyond its critical anti-elastase function, clearly evidenced by the development of chronic obstructive pulmonary disease (COPD) in deficient individuals, α-1-antitrypsin deficiency is implicated in control of airway inflammation since asthma symptoms are reported in α-1-antitrypsin deficiency [22,23,24]
Summary
Vitamin D is a potent anti-inflammatory mediator, with its active form (1,25-dihydroxyvitamin D, 1,25(OH)2D3) having a range of immune-regulatory functions including direct induction of anti-microbial functions and the generation of tolerogenic antigen presenting cells and regulatory T cells [1]. Mediated induction of the anti-inflammatory cytokine IL-10, the immune-suppressive ligand CD200 and the regulatory T cell hallmark transcription factor FoxP3 [2,3,4,5]. Associations exist between reduced α-1-antitrypsin expression and/or function and a number of human diseases of immune dysregulation [10]. As yet these properties of α-1-antitrypsin are not fully understood, but the cytokine IL-10 may play a key role. Subsequent studies investigated whether this represents a direct action of α-1-antitrypsin, or whether additional co-factors are required, as well as whether α-1-antitrypsin may be required for the immune regulatory functions, IL-10 induction, of 1,25(OH)2D3
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