Abstract
Invariant Natural Killer T (iNKT) cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases. We considered that immunometabolic factors might affect iNKT cell function. To this end, we investigated iNKT cell phenotype and function in a cohort of adolescents with chronic disease and immunometabolic abnormalities. We analyzed peripheral blood iNKT cells of adolescents with cystic fibrosis (CF, n = 24), corrected coarctation of the aorta (CoA, n = 25), juvenile idiopathic arthritis (JIA, n = 20), obesity (OB, n = 20), and corrected atrial septal defect (ASD, n = 25) as controls. To study transcriptional differences, we performed RNA sequencing on a subset of obese patients and controls. Finally, we performed standardized co-culture experiments using patient plasma, to investigate the effect of plasma factors on iNKT cell function. We found comparable iNKT cell numbers across patient groups, except for reduced iNKT cell numbers in JIA patients. Upon ex-vivo activation, we observed enhanced IFN-γ/IL-4 cytokine ratios in iNKT cells of obese adolescents versus controls. The Th1-skewed iNKT cell cytokine profile of obese adolescents was not explained by a distinct transcriptional profile of the iNKT cells. Co-culture experiments with patient plasma revealed that across all patient groups, obesity-associated plasma factors including LDL-cholesterol, leptin, and fatty-acid binding protein 4 (FABP4) coincided with higher IFN-γ production, whereas high HDL-cholesterol and insulin sensitivity (QUICKI) coincided with higher IL-4 production. LDL and HDL supplementation in co-culture studies confirmed the effects of lipoproteins on iNKT cell cytokine production. These results suggest that circulating immunometabolic factors such as lipoproteins may be involved in Th1 skewing of the iNKT cell cytokine response in immunometabolic disease.
Highlights
Invariant Natural Killer T cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases
cystic fibrosis (CF) is associated with visceral adipose tissue accumulation, which was reflected by a high waist-to-hip ratio (WHR) (Table 1)[12]
coarctation of the aorta (CoA) patients showed elevation of systolic blood pressure (SBP) characteristic for this patient population, and a higher WHR, which may be explained by the male predominance in this group
Summary
Invariant Natural Killer T (iNKT) cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases. Invariant Natural Killer T (iNKT) cells are a unique innate-like T cell subset that respond to lipid antigens presented on the MHCI-like molecule CD1d, and operate on the border of metabolic derangement and inflammation[1] As such, they have been implicated in immunometabolic diseases such as obesity, type II diabetes, and cardiovascular disease. In this study we investigated whether immunometabolic factors in chronic disease may affect iNKT cell phenotype and function in a diverse cohort of adolescents with inflammatory, metabolic, and hemodynamic abnormalities. We performed standardized co-culture experiments using THP-1 monocytes loaded with patient plasma as antigen presenting cells, in co-culture with healthy donor-derived short-term iNKT cell lines, to investigate the effect of plasma factors on iNKT cell function These experiments were followed by LDL and HDL supplementation studies. By analyzing iNKT cells in such a diverse cohort of adolescents with a range of immunometabolic abnormalities, we aimed to identify which inflammatory and metabolic factors are associated with skewing of the iNKT cell phenotype
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