Abstract
The complement regulator CD46 is a costimulatory molecule for human T cells that induces a regulatory Tr1 phenotype, characterized by large amounts of IL-10 secretion. Secretion of IL-10 upon CD46 costimulation is largely impaired in T cells from patients with multiple sclerosis (MS). Vitamin D can exert a direct effect on T cells, and may be beneficial in several pathologies, including MS. In this pilot study, we examined whether active vitamin D (1,25(OH)2D3 or calcitriol) could modulate the CD46 pathway and restore IL-10 production by CD46-costimulated CD4+ T cells from patients with MS. In healthy T cells, calcitriol profoundly affects the phenotype of CD46-costimulated CD4+ T cells, by increasing the expression of CD28, CD25, CTLA-4 and Foxp3 while it concomitantly decreased CD46 expression. Similar trends were observed in MS CD4+ T cells except for CD25 for which a striking opposite effect was observed: while CD25 was normally induced on MS T cells by CD46 costimulation, addition of calcitriol consistently inhibited its induction. Despite the aberrant effect on CD25 expression, calcitriol increased the IL-10:IFNγ ratio, characteristic of the CD46-induced Tr1 phenotype, in both T cells from healthy donors and patients with MS. Hence, we show that calcitriol affects the CD46 pathway, and that it promotes anti-inflammatory responses mediated by CD46. Moreover, it might be beneficial for T cell responses in MS.
Highlights
CD46 is a regulator of complement activity that binds to the C3b and C4b complement components, allowing their cleavage by factor I [1]
As CD46 costimulation is key in controlling IL-10 production and this pathway is defective in pathologies modulated by Vitamin D supplementation, we investigated whether calcitriol could modulate CD46 expression and function of activated T cells
We have recently shown that expression of CD46 at the cell surface of CD4+ T cells is tightly regulated by T cell activation, and that cleavage of CD46 ectodomain occurred upon its ligation in activated T cells [8,9]
Summary
CD46 is a regulator of complement activity that binds to the C3b and C4b complement components, allowing their cleavage by factor I [1]. CD46 binds to several pathogens [2] and promotes autophagy upon pathogen binding providing a crucial step in the control of infections [3]. CD46 is key in the regulation of the adaptive immune response. Costimulation with CD3/CD46 leads to increased T cell proliferation [4], regulates T cell mediated inflammation in a CD46-transgenic mouse model [5], induces morphological changes [6] and affects T cell polarity [7]. The enzymatic processing of CD46 is involved in the control of T cell homeostasis, by regulating activation and termination of T cell responses [8,9]. Defects in IL-10 production upon CD46 activation have been demonstrated in patients with MS [12,13,14], asthma [15] and rheumatoid arthritis [11]
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