SummaryAdult human mesenchymal stromal or stem cells (MSC) can differentiate into a variety of cell types and are candidate cellular therapeutics in regenerative medicine. Surprisingly, these cells also display multiple potent immunomodulatory capabilities, including allosuppression, making allogeneic cell therapy a possibility. The exact mechanisms involved in regulatory T cell induction by allogeneic human MSC was examined, using purified CD4
Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate inflammatory responses through the rapid production of cytokines. In this article, we show that circulating MAIT cells are depleted in obese adults, and depletion is associated with diabetic status. Circulating MAIT cells more frequently produced IL-17 upon stimulation ex vivo, a cytokine implicated in insulin resistance. MAIT cells were enriched in adipose tissue (AT) compared with blood. AT MAIT cells, but not circulating MAIT cells, were capable of producing IL-10. In AT from obese subjects, MAIT cells were depleted, were less likely to produce IL-10, and more frequently produced IL-17. Finally, we show that IL-17+ MAIT cells are also increased in childhood obesity, and altered MAIT cell frequencies in obese children are positively associated with insulin resistance. These data indicate that MAIT cells are enriched in human AT and display an IL-17+ phenotype in both obese adults and children, correlating with levels of insulin resistance. The alterations in MAIT cells may be contributing to obesity-related sterile inflammation and insulin resistance.
+ T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4 + T cell proliferation and reduction of human tumour necrosis factor-a in serum.
IntroductionMesenchymal stromal cells (MSC) have well defined immunomodulatory properties including the suppression of lymphocyte proliferation and inhibition of dendritic cell (DC) maturation involving both cell contact and soluble factors. These properties have made MSC attractive candidates for cellular therapy. However, the mechanism underlying these characteristics remains unclear. This study sought to investigate the mechanisms by which MSC induce a regulatory environment.MethodAllogeneic bone marrow mesenchymal stromal cells were cultured with T cells or dendritic cells in the presence or absence of gamma secretase inhibitor to block Notch receptor signalling. T cells and dendritic cells were examined by flow cytometry for changes in phenotype marker expression. Stable knock down MSC were generated to examine the influence of Jagged 1 signalling by MSC. Both wildtype and knockdown MSC were subsequently used in vivo in an animal model of allergic airway inflammation.ResultsThe Notch ligand Jagged-1 was demonstrated to be involved in MSC expansion of regulatory T cells (Treg). Additionally, MSC-induced a functional semi-mature DC phenotype, which further required Notch signalling for the expansion of Treg. MSC, but not Jagged-1 knock down MSC, reduced pathology in a mouse model of allergic airway inflammation. Protection mediated by MSC was associated with enhanced Treg in the lung and significantly increased production of interleukin (IL)-10 in splenocytes re-stimulated with allergen. Significantly less Treg and IL-10 was observed in mice treated with Jagged-1 knock down MSC.ConclusionsThe current study suggests that MSC-mediated immune modulation involves the education and expansion of regulatory immune cells in a Jagged-1 dependent manner and provides the first report of the importance of Jagged-1 signalling in MSC protection against inflammation in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0021-5) contains supplementary material, which is available to authorized users.
Obesity underpins the development of numerous chronic diseases, such as type II diabetes mellitus. It is well established that obesity negatively alters immune cell frequencies and functions. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells, which we have previously reported are dysregulated in obesity, with altered circulating and adipose tissue frequencies and a reduction in their IFN-g production, which is a critical effector function of MAIT cells in host defense. Hence, there is increased urgency to characterize the key molecular mechanisms that drive MAIT cell effector functions and to identify those which are impaired in the obesity setting. In this study, we found that MAIT cells significantly upregulate their rates of glycolysis upon activation in an mTORC1-dependent manner, and this is essential for MAIT cell IFN-g production. Furthermore, we show that mTORC1 activation is dependent on amino acid transport via SLC7A5. In obese patients, using RNA sequencing, Seahorse analysis, and a series of in vitro experiments, we demonstrate that MAIT cells isolated from obese adults display defective glycolytic metabolism, mTORC1 signaling, and SLC7A5 aa transport. Collectively, our data detail the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlight mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses.
Vgamma9Vdelta2 T cells respond to pyrophosphate antigens and display potent antitumour activity in vitro. We have investigated the potential of the most potent phosphoantigen known to activate Vgamma9Vdelta2 T cells, (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP), as an adjuvant for dendritic cell (DC)-based vaccines. A single stimulation of peripheral blood mononuclear cells with HMB-PP and IL-2 was sufficient to generate lines of effector memory Vgamma9Vdelta2 T cells that retained their cytolytic and cytokine secretion activities. These cells induced differentiation of DC into semi-mature antigen-presenting cells expressing CD86, CD11c, CD54, HLA-DR, CD83 and CD40, which secreted low levels of bioactive IL-12 but no IL-10. Vgamma9Vdelta2 T cells also strongly costimulated IL-12 release but inhibited IL-10 production by lipopolysaccharide (LPS)-stimulated DC. When substituted for Vgamma9Vdelta2 T cells, IFN-gamma did not induce full DC maturation but it augmented IL-12 and inhibited IL-10 release by LPS-stimulated DC, in a manner similar to HMB-PP-activated Vgamma9Vdelta2 T cells. Our findings indicate that Vgamma9Vdelta2 T cells, stimulated with nanomolar concentrations of HMB-PP, strongly promote T helper type 1 (Th1) responses through their ability to induce DC maturation and IL-12 secretion. This adjuvant activity may prove useful in DC-based cancer therapies.
High-grade PC secondary to appendiceal or colorectal adenocarcinoma can be managed with CRS/HIPEC. The number of LN metastases at the time of CRS/HIPEC is the strongest predictor of progression and must be considered when determining patient eligibility for this aggressive treatment.
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