Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.
Highlights
Vitamin D deficiency is a growing public health problem that is proposed as a contributing factor in several chronic inflammatory diseases
We highlight a key role of 1,25(OH)2D3, one of the most prevalent modifiable environmental factors in Multiple sclerosis (MS), in the regulation of inflammation by demonstrating its role in differentially modulating the expression of adhesion molecules involved in the migration of T cells to the central nervous system (CNS), depending on their activation pathways (Figure 10)
While we detected a decrease in b7-integrin expression, we observed a significant increase in CCR9 with addition of 1,25 (OH)2D3
Summary
Vitamin D deficiency is a growing public health problem that is proposed as a contributing factor in several chronic inflammatory diseases. The key role of the immune system in MS pathogenesis has been highlighted by genome-wide association studies [12], and the efficacy of immune-targeting therapeutic strategies, with a central role for T cells due to effector T cells (Teffs) that recognize auto-antigens and reduced numbers or impaired function of regulatory T cells Both Foxp3+ Tregs and Tr1, such as those induced by ligation of the complement regulator CD46 [13, 14], are dysregulated in MS [15,16,17]. Our data suggest that Vitamin D favors response to CD46-induced Tr1 cells through increased VDR expression and allowing a better response to Vitamin D that promotes Tr1 cells This represents a key mechanism to promote immuno-modulation in chronic inflammatory diseases, including MS
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
