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.
Corticotropin-releasing hormone (CRH) is a 41 amino acid neuropeptide which plays an important role in the stress response in the hypothalamus. We describe the development of an immortalized hypothalamic cell line which expresses CRH. We hypothesized that this cell line would possess the relevant characteristics of parvocellular CRH-expressing neurones such as glucocorticoid receptor (GR) expression and vasopressin (VP) coexpression. For production of hypothalamic cells, embryonic day 19 rat pup hypothalami were dissected and dissociated into tissue culture dishes. They were immortalized by retrovirus-mediated transfer of the SV40 large T antigen gene at 3 days of culture and then screened for expression of CRH following dilution cloning. One cell line was chosen (IVB) which exhibited CRH-like immunoreactivity (CRH-LI) and expressed CRH, VP and CRH 1 receptor RNA via the reverse transcriptase-polymerase chain reaction. In addition, the cell line expressed the neuronal marker, microtubule-associated protein-2. We veri®ed that the CRH-LI from IVB cell lysates coeluted with CRH standard via reversed-phase high-performance liquid chromatography (HPLC). Furthermore, oxidation of the lysate converted its HPLC pro®le to that identical with oxidized CRH standard. In addition, IVB cells exhibited high af®nity binding to CRH. Incubation of IVB cells with CRH lead to increases in cAMP levels and protein kinase A activity in a concentration-dependent manner. Incubation of IVB cells with CRH also resulted in increases in phospho-cyclic-AMP response element binding protein (CREB) imunostaining as detected by immunocytochemical analysis. Finally, CRH treatment of IVB cell lines has been linked to CREB-mediated gene expression as determined via the PathDetect CREB trans-reporting system. The characteristics of IVB cells, such as CRH and VP coexpression, GR expression and a biologically active CRH-R1-mediated signalling pathway, suggest that this neuronal cell line may serve as model of parvocellular CRH neurones.Corticotropin-releasing hormone (CRH) is a 41 amino acid containing neuropeptide which coordinates the neuroendocrine, behavioural, autonomic and immune responses to stress (1, 2). It is secreted from the hypothalamus and acts on pituitary corticotrophs to enhance secretion of adrenocorticotropic hormone (ACTH) and other pro-opiomelanocortin products. ACTH, in turn, stimulates glucocorticoid synthesis and secretion in the adrenal cortex. CRH containing parvocellular neurones coexpress vasopressin (VP) and are subject to negative feedback by glucocorticoids following stressful conditions (3).The cellular effects of CRH are mediated by high-af®nity receptors (4±7). In addition to the anterior and intermediate lobes of the pituitary (8), CRH receptors are located in a wide variety of locations in the central nervous system (CNS), including the parvocellular neurones of the paraventricular nucleus where they are induced by stress (9). There are two CRH receptor types.
Mucosal associated invariant T (MAIT) cells are a population of evolutionarily conserved T cells, which express an invariant T cell receptor (TCR) and represent a significant subset of innate-like T cells in humans, yet their role in immunity is still emerging. Unlike conventional αβ T cells, MAIT cells are not restricted by MHC molecules, but instead uniquely recognize microbially derived vitamin metabolites presented by the MHC-I like molecule MR1. MAIT cells are enriched in mucosal sites and tissues including liver andadipose tissue where they are thought to play an important role in immunosurveillance and immunity against microbial infection. In addition to their putative role in antimicrobial immunity, recent research on MAIT cells, in particular IL-17 producing MAIT cells, has demonstrated their involvement in numerous chronic inflammatory conditions. In this review, we give an overview of the work to date on the function and subsets of MAIT cells. We also examine the role of IL-17 producing MAIT cells in chronic inflammatory diseases ranging from autoimmune conditions, metabolic diseases to cancer. Furthermore, we discuss the most recent findings from the clinic that might help deepen our understanding about the biology of MAIT cells.
Mucosal Associated Invariant T (MAIT) cells are an abundant population of innate T cells which recognise bacterial ligands presented by the MHC class-I like molecule MR1. MAIT cells play a key role in host protection against bacterial and viral pathogens. Upon activation MAIT cells undergo proliferative expansion and increased production of effector molecules such as cytokines. The molecular and metabolic mechanisms controlling MAIT cell effector functions are still emerging. In this study, we found that expression of the key metabolism regulator and transcription factor MYC is upregulated in MAIT cells upon immune stimulation. Using quantitative mass spectrometry, we identified the activation of two MYC controlled metabolic pathways; amino acid transport and glycolysis, both of which are critical for MAIT cell proliferation. Finally, we show that MYC expression in response to immune activation is diminished in MAIT cells isolated from people with obesity, resulting in defective MAIT cell proliferation and functional responses. Collectively our data details for the first time the importance of MYC regulated metabolism for MAIT cell proliferation, and provides additional insight into the molecular defects underpinning functional failings of MAIT cells in obesity.
Natural killer (NK) cells are a population of innate immune cells which can rapidily kill cancer cells and produce cytokines such as interferon gamma (IFN-gamma). A key feature of NK cells is their ability to respond without prior sensitation, however it is now well established that NK cells can possess memory-like features. After activation with cytokines, NK cells demonstrate enhanced effector functions upon restimulation days or weeks later. This demonstrates that NK cells may be "trained" to be more effective killers and harnessed as more potent cancer immunotherapy agents. We have previously demonstrated that cellular metabolism is essential for NK cell responses, with NK cells upregulating both glycolysis and oxidative phosphorylation upon cytokine stimulation. Limiting NK cell metabolism results in reduced cytotoxicity and cytokine production. We have also demonstrated that defective NK cell responses in obesity are linked to defective cellular metabolism. In the current study we investigated if cellular metabolism is required during the initial period of NK cell cytokine training, and if NK cells from people with obesity (PWO) can be effectively trained. We show that increased flux through glycolysis and OXPHOS during the initial cytokine activation period is essential for NK cell training, as is the metabolic signalling factor Srepb. We show that NK cells from PWO, which are metabolically defective, display impaired NK cell training, which may have implications for immunotherapy in this particularly vulnerable group.
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