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Explorer Calcitriol modulates the CD 46 pathway in T cells

Profile image of Anne L AstierAnne L Astier

2017

https://doi.org/10.1371/JOURNAL.PONE.0048486
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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, addit...

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Calcitriol Modulates the CD46 Pathway in T Cells
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PLoS ONE, 2012

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: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.

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Vitamin D as an immune modulator in multiple sclerosis, a review
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The role of vitamin D in calcium homeostasis is well known. More recently vitamin D has become a topic of interest in immune regulation and multiple sclerosis. The main reason for this is the observed geographical distribution of multiple sclerosis. Areas with high sunlight exposure, the principal inducer of vitamin D synthesis, have a relatively low prevalence of multiple sclerosis and vice versa. Furthermore, low levels of the principal vitamin D metabolite (25-hydroxy vitamin D) in the circulation are associated with a high incidence of multiple sclerosis. Other epidemiological evidence also supports the view that vitamin D metabolites have an immune and disease modulating effect in multiple sclerosis. Experimental research in vitro and in animal models has further clarified the interaction of vitamin D metabolites with the immune system. The evidence obtained from these studies strongly supports a model in which vitamin D mediates a shift to a more anti-inflammatory immune response, and in particular to enhanced regulatory T cell functionality. In the current review we link the basic knowledge on vitamin D and immune regulation with the vitamin D related observations in multiple sclerosis. We conclude that there is a sound basis on which to initiate double-blind placebo-controlled trials that not only address the effect of vitamin D on the clinical outcome of multiple sclerosis, but also on the regulatory T cell compartment.

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Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis
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Vitamin D as a Potential Therapy for Multiple Sclerosis: Where Are We?
isha sharma

International Journal of Molecular Sciences

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is caused by an aberrant immune response to myelin sheath. Disease-modifying medications, which mainly aim to suppress such aberrant immune response, have significantly improved MS treatment. However, the disease severity continues to worsen. In contrast, progressively more data suggest that 1,25-dihydroxyvitamin D or 1,25(OH)2D, i.e., the active vitamin D, suppresses the differentiation of potentially pathogenic T cells associated with MS, enhances the differentiation of regulatory T cells that suppress the pathogenic T cells, and promotes remyelination. These novel 1,25(OH)2D functions have encouraged investigators to develop vitamin D as a potential therapy for MS. However, because of the hypercalcemia that is associated with high 1,25(OH)2D concentrations, supplementation of native vitamin D has been a major focus in clinical trials for the treatment of MS, but such trials have produced ...

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The Vitamin D Analog, TX527, Promotes a Human CD4+CD25highCD127low Regulatory T Cell Profile and Induces a Migratory Signature Specific for Homing to Sites of Inflammation
Annemieke Verstuyf

The Journal of Immunology, 2011

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Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
Evaggelia Liaskou

Scientific Reports

The CD28 locus is associated with susceptibility to a variety of autoimmune and immune-mediated inflammatory diseases including primary sclerosing cholangitis (PSC). Previously, we linked the CD28 pathway in PSC disease pathology and found that vitamin D could maintain CD28 expression. Here, we assessed whether the PSC-associated CD28 risk variant A (rs7426056) affects CD28 expression and T cell function in healthy individuals (n = 14 AA, n = 14 AG, n = 14 GG). Homozygotes for the PSC disease risk allele (AA) showed significantly lower CD28 mRNA expression ex-vivo than either GG or AG (p < 0.001) in total peripheral blood mononuclear cells. However, the CD28 risk variant alone was not sufficient to explain CD28 protein loss on CD4 + T cells. All genotypes responded equally to vitamin D as indicated by induction of a regulatory phenotype and an increased anti-inflammatory/pro-inflammatory cytokine ratio. A genotypic effect on response to TNFα stimuli was detected, which was inhibited by vitamin D. Together our results show: (a) an altered gene expression in carriers of the susceptible CD28 variant, (b) no differences in protein levels on CD4 + T cells, and (c) a protective effect of the variant upon CD28 protein loss on CD4 + T cells under inflammatory conditions.

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{"__content__"=>"Complement receptor CD46 co-stimulates optimal human CD8 T cell effector function via fatty acid metabolism.", "sup"=>{"__content__"=>"+"}}
Paul Lavender

Nature communications, 2018

The induction of human CD4 Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4 T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8 T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.

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Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases
Bingze Xu

Proceedings of the National Academy of Sciences, 2020

Significance Conclusive identification of single genes contributing to complex autoimmune diseases has been challenging. Here, we positionally identify the vitamin D3 receptor gene ( Vdr ) as a driver of T cell-dependent inflammatory diseases using forward genetics. In the process, we generated congenic mice that overexpress Vdr in T cells as a consequence of natural polymorphisms in its promoter. These mice present a unique opportunity to study the immunomodulatory properties of VDR in a physiological setting. Moreover, the restricted overexpression of VDR to immune cells allows discrimination between immune-acting and confounding musculoskeletal effects of VDR. Our results suggest that VDR plays a role in T cell activation in parallel to the antiinflammatory actions mediated by its ligand.

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Monocyte:T‐cell interaction regulates human T‐cell activation through a CD28/CD46 crosstalk
Anne L Astier

Immunology &amp; Cell Biology, 2015

T‐cell activation requires engagement of the T‐cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T‐cell activation was reported several decades ago and the molecular mechanisms involved have now been well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T‐cell differentiation from producing some IFNγ to secreting some potent anti‐inflammatory IL‐10, acquiring a so‐called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T‐cell activation and IL‐10 production. The observation that CD46 cleavage was reduced when PBMCs were costimulated compared with purified CD4+ T cells led us to hypothesize that interactions between different cell types within the PBMCs were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4+ T cells are cocultured with autologous mo...

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