Targeting mitochondrial dysfunction in MAIT cells limits IL-17 production in obesity

Brien, Aisling O'; Kedia-Mehta, Nidhi; Tobin, Laura; Veerapen, Natacha; Besra, Gurdyal S.; Shea, Donal O'; Hogan, Andrew E.

doi:10.1038/s41423-020-0375-1

Cited by 29 publications

(25 citation statements)

References 10 publications

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“…EDTA-blood was diluted 1:1 with phosphate buffered saline (PBS, Hyclone) and purified by density-gradient centrifugation with Lymphoprep™ (AXIS-SHIELD). PBMCs were cultured in RPMI 1640 medium (Hyclone) containing 10% fetal bovine serum (FBS, Gibco) with 100 units/ml of penicillin (Gibco) at a concentration of 1 × 10 6 cells/ml in a 37°C cell culture incubator with 5% CO2.Expression levels of cytokines were detected by intracellular cytokines protocol as previously described ( 29 , 30 ). Freshly drawn peripheral blood samples were stimulated for 5 h with 250 ng/ml PMA (Sigma) and 1 μg/ml ionomycin (PeproTech).…”

Section: Methodsmentioning

confidence: 99%

Mucosal Associated Invariant T Cells Were Activated and Polarized Toward Th17 in Chronic Obstructive Pulmonary Disease

Qiu

Kang

et al. 2021

Front. Immunol.

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Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by airway limitation accompanied with infiltration of inflammatory cells. Mucosal associated invariant T (MAIT) cells can recognize bacteria and play an important role in controlling host immune responses by producing cytokines. In this study, we characterized the function and the ability of MAIT cells to secrete cytokines measured by flow cytometry. In COPD patients, MAIT cells have the ability to produce more IL-17 and less IFN-γ compared to healthy individuals. We found that HLA-DR expression levels reflected the degree of inflammation and the proportion of IL-17 was significantly correlated with lung function in peripheral blood. In addition, we found that MAIT cells were highly expressed in the lung, and the increased expression of CXCR2, CXCL1 indicated that MAIT cells had the potential to migrate to inflammatory tissues. This evidence implies that MAIT cells may play a potential role in COPD immunopathology.

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Section: Methodsmentioning

confidence: 99%

Mucosal Associated Invariant T Cells Were Activated and Polarized Toward Th17 in Chronic Obstructive Pulmonary Disease

Qiu

Kang

et al. 2021

Front. Immunol.

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“…Therefore, due to their increased effector functions and positive clinical trials, cytokine trained NK cells represent an attractive therapeutic option for PWO. However, we have previously demonstrated that the cellular metabolism of several immune subsets are severely defective in obesity 11,12,41,42 . NK cells from PWO fail to engage in metabolic reprogramming, due to the obesogenic microenvironment that leads to lipid overload, which underpins the reported defects in their functional responses 12 .…”

Section: Discussionmentioning

confidence: 99%

Cytokine-induced natural killer cell training is dependent on cellular metabolism and is defective in obesity

et al. 2021

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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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“…Tissue MAIT cells may rely on OXPHOS, which correlates with TNF and IL-17 production in their circulating counterparts (96,98). Given low tissue glucose concentrations, many resident immune cells are adapted to oxidative phosphorylation of fatty acids abundant in the skin and intestine (99).…”

Section: Barrier Adaptation Metabolismmentioning

confidence: 99%

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

et al. 2020

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Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus. Tissue-specific and adapted functions of barrier immune cells are shaped by transcriptional programs and regulated through a blend of local cellular, inflammatory, physiological, and metabolic mediators unique to each microenvironment. This review compares the phenotype and function of MAIT cells with other barrier immune cells, highlighting potential areas for future exploration. Appreciation of MAIT cell biology within tissues is crucial to understanding their niche in health and disease.

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Targeting mitochondrial dysfunction in MAIT cells limits IL-17 production in obesity

Cited by 29 publications

References 10 publications

Mucosal Associated Invariant T Cells Were Activated and Polarized Toward Th17 in Chronic Obstructive Pulmonary Disease

Mucosal Associated Invariant T Cells Were Activated and Polarized Toward Th17 in Chronic Obstructive Pulmonary Disease

Cytokine-induced natural killer cell training is dependent on cellular metabolism and is defective in obesity

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

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