scholarly journals Vitamin D Deficiency Contributes to the Reduction and Impaired Function of NaïveCD45RA+Regulatory T Cell in Chronic Heart Failure

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Yan-hui Ma ◽  
Yun-lan Zhou ◽  
Chao-yan Yue ◽  
Guang-hui Zhang ◽  
Lin Deng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Vitamin D ◽  
T Cell ◽  
Chronic Heart Failure ◽  
Cardiovascular Health ◽  
Cell Function ◽  
Foxp3 Expression ◽  
Vitamin D Supplementation ◽  
The Impact

The effect of vitamin D pertinent to cardiovascular health on the heart itself is considered to shift toward an anti-inflammatory response in chronic heart failure (CHF); however, its underlying mechanism is not completely understood. In this study, we demonstrated that plasma 25(OH)D level, negatively associated with NT-ProBNP, correlated with the decreased Treg in CHF compared to the patients with other cardiovascular diseases and healthy and older donors. Naïve Treg cell (CD4+CD45RA+Foxp3loT) subset, rather than whole Treg cells, contributes to the reduction of Treg in CHF. 1,25(OH)2D treatment maintained partial expression of CD45RA on CD4+T cell afterαCD3/CD28 monoclonal antibodies activation and ameliorated the impaired CD4+CD45RA+T cell function from CHF patients through upregulating Foxp3 expression and IL-10 secretionin vitro. Low level of vitamin D receptor (VDR) was detected in CD4+CD45RA+T cell of CHF than control, while 1,25(OH)2D treatment increased the VDR expression to exert its immunosuppression on T cell. The results of this study might provide tangible evidence to our knowledge of the impact of vitamin D supplementation on naïve Tregs, which may offer new means of preventing and treating CHF.

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

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.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

scholarly journals Effects of 1,25-dihydroxyvitamin D3 on Inflammatory Responses of Stromal Vascular Cells and Adipocytes from Control and Obese Mice (FS12-04-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Chan Yoon Park ◽  
Tae Yeon Kim ◽  
Yeonkyung Seo ◽  
Ji Su Yoo ◽  
Munkyong Pae ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
T Cell ◽  
Immune Cells ◽  
Inflammatory Cytokine ◽  
Nk Cell ◽  
Vitamin D Supplementation ◽  
Mrna Levels ◽  
Dihydroxyvitamin D3

Abstract Objectives Several in vitro studies showed that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment could inhibit chronic inflammation in mouse or human adipocytes; however there have been a few in vivo studies. We investigated whether vitamin D supplementation affects subpopulation of immune cells in adipose tissue and the effects of in vitro 1,25(OH)2D3 treatment on pro-inflammatory cytokine secretion by stromal vascular cells (SVC) and adipocytes. Methods Five-wk old C57BL/6 N mice were divided into 4 groups and fed diets differ in fat amount (10 or 45% kcal fat: CON or HFD) and vitamin D content (1000 or 10,000 IU/kg of diet: DC, or DS) for 13 wks. Subpopulation of immune cells (macrophage, NK cell, CD 4 T cell, CD 8 T cell, B cell) from adipose tissue-derived SVC was determined by FACS analysis. Five-wk old C57BL/6 mice were fed control or HFD diets (10 or 60% kcal fat, CON or HFD) for 12 wks. Adipocytes and SVC, isolated from visceral adipose tissue, were cultured with or without 10 nM of 1,25(OH)2D3 for 48 h and stimulated with LPS during the last 24 h. Pro-inflammatory cytokines produced by SVC and adipocytes were measured by ELISA. The mRNA levels of Tlr2, Tlr4, Dusp1, and Dusp10 were determined in SVC by real-time PCR. Results The number of macrophages and NK cells within adipose tissue were higher in the HFD groups than CON groups. Dietary vitamin D did not alter the number of immune cells in adipose tissue. The production of IL-6 and MCP-1 from SVC and adipocytes were higher in the HFD groups compared with CON groups. In vitro 1,25(OH)2D3 treatment decreased IL-6, MCP-1, IL-1β production by SVC from HFD group and decreased IL-6 production by SVC from CON group. SVC Tlr2 mRNA levels, which were higher in the HFD group, decreased significantly by in vitro 1,25(OH)2D3 treatment. mRNA levels of Dusp1, which inhibits MAPK signaling, were increased by in vitro 1,25(OH)2D3 treatment. However, pro-inflammatory cytokine secretion from adipocytes was not affected by in vitro 1,25(OH)2D3 treatment. Conclusions Although vitamin D supplementation did not reduce macrophage and NK cell numbers in adipose tissue, 1,25(OH)2D3 seemed to decrease pro-inflammatory cytokine production from SVCs by regulating Tlr2 and Dusp1. Funding Sources Supported by the grant from the National Research Foundation (NRF) of Korea (NRF-2018R1D1A1B070491).

scholarly journals Th17 Cell Enhances CD8 T-Cell Cytotoxicity via IL-21 Production in Emphysema Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Min-Chao Duan ◽  
Ying Huang ◽  
Xiao-Ning Zhong ◽  
Hai-Juan Tang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Response ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Cell Function ◽  
Cytotoxic T Cell ◽  
Protein Levels ◽  
The Impact

Emphysema is a T-cell mediated autoimmune disease caused predominantly by cigarette smoking. Th17 cells and related cytokines may contribute to this disorder. However, the possible implication of Th17 cells in regulating inflammatory response in emphysema remains to be elucidated. In the current study, we tested the protein levels of IL-17 and IL-21 in peripheral blood and lung tissues from cigarette-smoke- (CS-) exposed mice and air-exposed mice, analyzed the frequencies of CD4+IL-17+(Th17) cells, IL-21+Th17 cells, and CD8+IL-21R+T cells in peripheral blood and lung tissues of mice, and their relationship with emphysematous lesions, and explored the impact of IL-21 on cytotoxic CD8+T cells functionin vitro.It was found that the frequencies of Th17, IL-21+Th17, and CD8+IL-21R+T cells and the levels of IL-17 and IL-21 of CS-exposed mice were much higher than those of the air-exposed mice and correlated with emphysematous lesions. Additionally, the number of IL-21+Th17 cells positively correlated with the number of CD8+IL-21R+T cells. Thein vitroexperiments showed that IL-21 significantly augmented the secretion of perforin and granzyme B in CD8+T cells from CS-exposed mice. These data indirectly provide evidence that Th17 cells could be involved in the control of the local and system inflammatory response in emphysema by regulating CD8+cytotoxic T-cell function.

scholarly journals IAP inhibitors enhance co-stimulation to promote tumor immunity

2010 ◽  
Vol 207 (10) ◽  
pp. 2195-2206 ◽  
Author(s):  
Michael Dougan ◽  
Stephanie Dougan ◽  
Joanna Slisz ◽  
Brant Firestone ◽  
Matthew Vanneman ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic Activity ◽  
Small Molecule ◽  
Cell Function ◽  
Tumor Vaccine ◽  
Nuclear Factor Κb ◽  
Cell Responses ◽  
The Impact

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.

scholarly journals Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells

2013 ◽  
Vol 210 (2) ◽  
pp. 257-268 ◽  
Author(s):  
Wing-hong Kwan ◽  
William van der Touw ◽  
Estela Paz-Artal ◽  
Ming O. Li ◽  
Peter S. Heeger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Foxp3 Expression ◽  
C5a Receptor ◽  
Self Tolerance ◽  
T Cell Immune Responses

Thymus-derived (natural) CD4+ FoxP3+ regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4+CD25− T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.

Sign in / Sign up

Export Citation Format

Share Document