Indoleamine 2,3-Dioxygenase (IDO) Enzyme Links Innate Immunity and Altered T-Cell Differentiation in Non-ST Segment Elevation Acute Coronary Syndrome.

Chiara Zara,Claudia Lucci,Domenico D’Amario,Ramona Vinci,Davide Flego,Giulio La Rosa,Anna Severino,Filippo Crea,Ada Giglio,Giovanna Liuzzo,Eugenia Pisano,Francesco Trotta,Luigi Biasucci,Aureliano Ruggio,Daniela Pedicino

doi:10.3390/ijms19010063

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by a complex interplay between innate and adaptive immunity. Dendritic cells (DCs) play a key role in T-cell activation and regulation by promoting a tolerogenic environment through the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme involved in tryptophan catabolism. IDO expression and activity was analyzed in monocytes derived DCs (MDDCs) from non-ST segment elevation myocardial infarction (NSTEMI) patients, stable angina (SA) patients and healthy controls (HC) by real-time quantitative polymerase chain reaction (RT-qPCR) before and after in vitro maturation with lipopolysaccharide (LPS). The amount of tryptophan catabolite; kynurenine; was evaluated in the culture supernatants of mature-MDDCs by ELISA assay. Autologous mixed lymphocyte reaction (MLR) between mature-MDDCs and naïve T-cells was carried out to study the differentiation towards T-helper 1 (Th1) and induced regulatory T-cells (iTreg). Analysis of IDO mRNA transcripts in mature-MDDCs revealed a significant reduction in cells isolated from NSTEMI (625.0 ± 128.2; mean ± SEM) as compared with those from SA (958.5 ± 218.3; p = 0.041) and from HC (1183.6 ± 231.6; p = 0.034). Furthermore; the concentration of kynurenine was lower in NSTEMI patients (2.78 ± 0.2) and SA (2.98 ± 0.25) as compared with HC (5.1 ± 0.69 ng/mL; p = 0.002 and p = 0.016; respectively). When IDO-competent mature-MDDCs were co-cultured with allogeneic naïve T-cells, the ratio between the percentage of generated Th1 and iTreg was higher in NSTEMI (4.4 ± 2.9) than in SA (1.8 ± 0.6; p = 0.056) and HC (0.9 ± 0.3; p = 0.008). In NSTEMI, the tolerogenic mechanism of the immune response related to IDO production by activated MDDCs is altered, supporting their role in T-cell dysregulation.

Highlights

The early outcome of acute coronary syndromes (ACS) has recently considerably improved, cardiovascular diseases still represent the leading cause of mortality worldwide.An adaptive immunity imbalance, mostly involving CD4+ T-cell subsets, has been documented among ACS with systemic evidence of inflammation [1]
We studied markers of monocyte-derived Dendritic cells (DCs) (MDDC) maturation, the expression of IDO and the kynurenine pathway in monocytes derived DCs (MDDCs) from patients presenting with non-ST segment elevation myocardial infarction (NSTEMI), stable angina (SA) and healthy controls (HC) after stimulation with lipopolysaccharide (LPS)
MDDC Maturation was Altered in NSTEMI Patients 2.1

Summary

Introduction

Mostly involving CD4+ T-cell subsets, has been documented among ACS with systemic evidence of inflammation [1]. T-cells from ACS patients show T-cell receptor (TCR) signaling abnormalities leading to enhanced immune response and altered T helper differentiation [5,6]. Atherosclerotic lesions contain abundant innate immune cells, including antigen presenting cells (APCs) that take part in initiation, progression and destabilization of the atherosclerotic plaque [7]. Dendritic cells (DCs) are a heterogeneous pool of professional APCs with the ability to sense a wide array of stimuli and translate innate into adaptive immunity by directing an appropriate T-cell response [8,9]

Methods

Results

Conclusion