Explorer Calcitriol modulates the CD 46 pathway in T cells

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:IFNc 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 antiinflammatory responses mediated by CD46. Moreover, it might be beneficial for T cell responses in MS. Citation: Kickler K, Ni Choileain S, Williams A, Richards A, Astier AL (2012) Calcitriol Modulates the CD46 Pathway in T Cells. PLoS ONE 7(10): e48486. doi:10.1371/ journal.pone.0048486 Editor: Pablo Villoslada, Institute Biomedical Research August Pi Sunyer (IDIBAPS) – Hospital Clinic of Barcelona, Spain Received July 12, 2012; Accepted October 2, 2012; Published October 29, 2012 Copyright: 2012 Kickler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a research grant from the MS Society to ALA (859/07). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: a.astier@ed.ac.uk