The Immunoregulatory Enzyme Indoleamine 2,3-Dioxygenase (IDO1) Is Expressed by Natural Killer (NK) Cells During Cytokine-Mediated Activation

吲哚胺2,3-双加氧酶 生物 细胞因子 自然杀伤细胞 白细胞介素12 免疫系统 犬尿氨酸 分子生物学 细胞毒性T细胞 免疫学 生物化学 体外 色氨酸 氨基酸
作者
Cecilia Evangelisti,Antonio Curti,Sara Trabanelli,Darina Očadlíková,Michele Baccarani,Roberto M. Lemoli
出处
期刊:Blood [Elsevier BV]
卷期号:116 (21): 3894-3894
标识
DOI:10.1182/blood.v116.21.3894.3894
摘要

Abstract Abstract 3894 Introduction: human NK cells are large, granular cells derived from lymphocyte lineage. They are critical mediators of the innate immunity as they rapidly respond to pathogens infected and tumour cells through cytotoxic and cytokines-producing responses. Indoleamine 2,3-dioxygenase (IDO1) is an enzyme catalyzing the degradation of the essential amino acid L-tryptophan into kynurenines. Several cell types, including dendritic cells, have been shown to express IDO1, which acts as a potent immunosuppressive agent. Recently, in addiction to IDO1, the new variant IDO2 was described but its immunosuppressive role is still under investigations. The aim of the present work is to study the expression and the role of IDO1 and IDO2 in NK cells. Methods: CD3-CD56+NK cells were immunomagnetically purified from healthy donors. IFN-gamma production was measured by ELISA assay. IDO1 and DAP12 transcript levels were normalized on ABL. IDO2 expression was measured by semi-quantitative PCR. Kynurenine levels were evaluated by colorimetric assay. Results: peripheral blood NK cells were treated with IL-2 for 16h, 40h, 88h and 160h. At the end of each IL-2 stimulation, supernatants were collected and IFN-gamma production was measured by colorimetric assay. IDO1 expression in NK cells was evaluated by quantitative real-time PCR and Western blotting. Our data show that, during IL-2-mediated activation, IDO1 is up-regulated at mRNA and protein levels. This effect is maximum after an overnight incubation and it decreases at later time points. IDO1 expression is clearly correlated with IFN-gamma production by NK cells whereas IFN-gamma receptor expression is not affected. Culturing NK cells with a combination of IL-2 and anti-IFN-gamma antibody demonstrated that IDO1 expression is regulated, at least in part, by IFN-gamma. Interestingly, IDO1 mRNA upregulation is associated with downregulation of DAP12, a gene whose expression has been showed to be inversely correlated to IDO1 in dendritic cells. IDO2 expression seems to be not affected by IL-2 stimulation. Treatment with other inflammatory cytokines demonstrated that IDO1 is modulated by different stimuli. Overnight incubation with IL-12, IFN-gamma and a combination of IL-2 and IL-6 showed IDO1 induction. IFN-gamma showed the highest IDO1 induction at transcript and protein level and, surprisingly, of IDO2 expression. IDO1 expression by NK cells resulted in increased production of kynurenines and this effect was abrogated by the addition of the IDO1 inhibitor 1-methyl tryptophan. Conclusion: our results demonstrate that NK cells upregulate IDO1 expression during cytokine-mediated activation and that IDO1 expression is regulated, at least in part, by IFN-gamma. Similarly to DCs, NK cells express IDO1 gene in association with DAP12, thus suggesting a common regulatory pathway among different cell subsets. Disclosures: Baccarani: NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

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