title: Calcitriol modulates the CD46 pathway in T cells.
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)(2)D(3) 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.
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Karoline
authors.initials: K
authors.lastname: Kickler
authors.forename: Siobhan
authors.initials: S
authors.lastname: Ni Choileain
authors.forename: Anna
authors.initials: A
authors.lastname: Williams
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
authors.forename: Anne L
authors.initials: AL
authors.lastname: Astier
mesh_terms: D000328:Adult; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D002117:Calcitriol / Q000276:immunology* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051916:Membrane Cofactor Protein / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014815:Vitamins / Q000276:immunology / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D051916:Membrane Cofactor Protein; D014815:Vitamins; D016753:Interleukin-10; D007371:Interferon-gamma; D002117:Calcitriol