Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

IFN-β treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-β and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-β, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-β, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-β and provide the bases for further mechanistic insights into these commonly used treatments.

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Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis

Frontiers in Immunology ◽

10.3389/fimmu.2020.598727 ◽

2020 ◽

Vol 11 ◽

Author(s):

Justin Killick ◽

Joanne Hay ◽

Elena Morandi ◽

Sonja Vermeren ◽

Saniya Kari ◽

...

Keyword(s):

Multiple Sclerosis ◽

Vitamin D ◽

T Cells ◽

T Cell ◽

Chronic Inflammatory Disease ◽

Vitamin D Supplementation ◽

Type I ◽

T Cell Migration ◽

The Impact

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.

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Investigations on T cell transmigration in a human skin-on-chip (SoC) model

Lab on a Chip ◽

10.1039/d0lc01194k ◽

2021 ◽

Vol 21 (8) ◽

pp. 1527-1539

Author(s):

Xiaoou Ren ◽

Anthony E. Getschman ◽

Samuel Hwang ◽

Brian F. Volkman ◽

Thomas Klonisch ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Human Skin ◽

Drug Candidates ◽

New Drug ◽

Human T Lymphocytes ◽

Quantitative Studies ◽

Inflammatory Skin ◽

Skin Conditions ◽

On Chip

Our skin-on-chip (SoC) model uniquely enabled quantitative studies of transendothelial and transepithelial migration of human T lymphocytes under mimicked inflammatory skin conditions and was used to test new drug candidates.

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Redox imbalance of red blood cells impacts T lymphocyte homeostasis: implication in carotid atherosclerosis

Thrombosis and Haemostasis ◽

10.1160/th11-02-0110 ◽

2011 ◽

Vol 106 (12) ◽

pp. 1117-1126. ◽

Cited By ~ 13

Author(s):

Brigitta Buttari ◽

Linda Petrone ◽

Elisabetta Straface ◽

Lucrezia Gambardella ◽

Donatella Pietraforte ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Red Blood Cells ◽

Blood Cells ◽

Healthy Subjects ◽

Carotid Atherosclerosis ◽

Cell Function ◽

Inflammatory Responses ◽

Activated T Lymphocytes

SummaryOxidative stress and immune/inflammatory responses are key pathogenetic factors of atherosclerotic disease. In this contest, mechanisms that regulate survival and death of immune cells may be relevant. Previous studies have demonstrated that red blood cells (RBCs) are physiologically able to inhibit apoptosis and to promote proliferation of activated T lymphocytes from healthy subjects. The aim of the present study was to evaluate whether RBCs from patients with carotid atherosclerosis maintain their property to modulate T cell homeostasis. Peripheral blood lymphocytes (PBLs) obtained from healthy subjects were activated in vitro by phytohemagglutinin in the presence/absence of RBCs from patients with carotid atherosclerosis or of in vitro oxidised RBCs from healthy subjects. Levels of reactive oxygen species (ROS) and aging markers of RBCs as well as susceptibility to apoptosis of PBLs were evaluated by flow cytometry. PBL proliferation was evaluated by 3H-methyl-thymidine incorporation assay whereas secretion of cytokines, analysed in view of their key role in T cell function, was assessed by ELISA. Levels of ROS and phosphatidyl-serine externalisation, a sign of RBC aging, resulted significantly higher in RBCs from patients than in those from healthy subjects, whereas surface glycophorin A expression and reduced glutathione content did the opposite. Unlike RBCs obtained from healthy subjects, RBCs from patients and in vitro oxidised RBCs did not protect activated T lymphocytes from apoptosis. Hence, RBCs from patients with carotid atherosclerosis, probably due to their oxidative imbalance, impact T cell integrity and function. Our results suggest a new regulatory role for RBCs in atherosclerosis.

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Immunological and genetic indices in workers under long-term exposure to low-doses of acrylonitrile

Hygiene and Sanitation ◽

10.47470/0016-9900-2021-100-10-1115-1122 ◽

2021 ◽

Vol 100 (10) ◽

pp. 1115-1122

Author(s):

Nina V. Zaitseva ◽

Tatyana S. Ulanova ◽

Oleg V. Dolgikh ◽

Tatyana V. Nurislamova ◽

Olga A. Kazakova ◽

...

Keyword(s):

T Lymphocytes ◽

Malonic Dialdehyde ◽

Test Group ◽

Invasive Procedure ◽

Low Doses ◽

Non Invasive ◽

Exhaled Air ◽

Activated T Lymphocytes ◽

The Impact

Introduction. Nowadays there is very relevant research on the study of the characteristics of the impact on the health of workers of low levels of harmful factors (acrylonitrile) of production during long-term exposure. Aim of the study was to examine peculiarities of immunologic and genetic indices in workers under the long-term exposure to acrylonitrile in low doses. Materials and methods. Our research object was working area air (MPCw.ar.=0.5 mg/m3) and biological media (blood and exhaled air) of workers employed at industrial rubber manufacture. Acrylonitrile was determined via a non-invasive procedure in exhaled air with samples being concentrated on sorption tubes that were then analyzed with capillary gas chromatography. Blood samples were examined to determine contents of malonic dialdehyde, lymphocytes (absolute and relative activated T-lymphocytes CD3+CD25+, absolute and relative activated T-lymphocytes CD3+CD95+), cytokines (VEGF), oncomarkers (PSA), and adrenals hormones; to do that, we applied ELISA tests and flow cytometry. Results. Acrylonitrile was established to occur in working area air in concentrations varying within MPCw.ar. range (0.007-0.015 mg/m3) being 2-3 times higher than in air inside offices at the same enterprise. We obtained statistically significant linear dependence between concentrations of acrylonitrile in the air exhaled by workers (y) and their working experience (x) that was given with the following equation: y=0.00046+0.00027x. According to the results of the laboratory examination of the workers, violations of the antioxidant defense were established. Contents of malonic dialdehyde and steroid hormones including progesterone, estradiol, and hydrocortisone that were pathogenetically linked to each other were authentically up to 3.2 times higher in the test group than in the reference one (p<0.05). Risk for antioxidant protection disorders such as elevated malonic dialdehyde contents in blood plasma might occur in the test group was 1.58 times higher than in the reference one. Conclusion. We revealed certain peculiarities in polymorphism of PPARGC1A Gly482Ser rs8192678 gene, the variability of which contributes to the formation of pathology of the cardiovascular, endocrine systems, oncoproliferative states that increase the likelihood of these undesirable events.

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Human T lymphocytes express N-methyl-d-aspartate receptors functionally active in controlling T cell activation

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2005.10.164 ◽

2005 ◽

Vol 338 (4) ◽

pp. 1875-1883 ◽

Cited By ~ 58

Author(s):

Gianluca Miglio ◽

Federica Varsaldi ◽

Grazia Lombardi

Keyword(s):

T Cell ◽

T Lymphocytes ◽

T Cell Activation ◽

Cell Activation ◽

Human T Lymphocytes

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Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility toCitrobacter rodentiumby suppressing mucosal Th17 responses

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00320.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. G1299-G1311 ◽

Cited By ~ 58

Author(s):

Natasha R. Ryz ◽

Scott J. Patterson ◽

Yiqun Zhang ◽

Caixia Ma ◽

Tina Huang ◽

...

Keyword(s):

Vitamin D ◽

Immune Responses ◽

Bacterial Pathogen ◽

Enteric Bacteria ◽

Host Susceptibility ◽

Active Vitamin ◽

Active Vitamin D ◽

Increased Risk ◽

The Impact

Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)2D3to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25(OH)2D3treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)2D3-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)2D3-treated mice showed defects in their production of the antimicrobial peptide REG3γ. Taken together, these studies show that 1,25(OH)2D3suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen.

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Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00249.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. G793-G803 ◽

Cited By ~ 34

Author(s):

Hongchun Liu ◽

Neal R. Patel ◽

Lewins Walter ◽

Sarah Ingersoll ◽

Shanthi V. Sitaraman ◽

...

Keyword(s):

Intestinal Epithelium ◽

Proinflammatory Cytokine ◽

Constitutive Expression ◽

Clinical Score ◽

Underlying Mechanism ◽

Chronic Inflammatory Disease ◽

Simultaneous Increase ◽

Colonic Tissue ◽

Acute Colitis ◽

Increased Risk

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)- and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSS- and S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc.

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The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity

Scientific Reports ◽

10.1038/s41598-020-74368-3 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Laia Gorchs ◽

Sultan Ahmed ◽

Chanté Mayer ◽

Alisa Knauf ◽

Carlos Fernández Moro ◽

...

Keyword(s):

Vitamin D ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Immune Surveillance ◽

Tumour Cell Line ◽

Prostaglandin E ◽

Cell Mediated Immunity ◽

Pancreatic Tumour ◽

The Impact

Abstract The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.

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The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain

Frontiers in Immunology ◽

10.3389/fimmu.2020.612104 ◽

2020 ◽

Vol 11 ◽

Author(s):

Patrick Süß ◽

Tobias Rothe ◽

Alana Hoffmann ◽

Johannes C. M. Schlachetzki ◽

Jürgen Winkler

Keyword(s):

Rheumatoid Arthritis ◽

Current Knowledge ◽

Later Life ◽

Chronic Inflammatory Disease ◽

Peripheral Inflammation ◽

Cellular Mechanisms ◽

Increased Risk ◽

Neuropsychiatric Diseases ◽

Patients At Risk ◽

The Impact

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases.

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