Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis.
Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis.
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DOI：
10.1002/art.40399
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Dooms H
中科院分区：
文献类型：
--
作者：
Fleury M;Belkina AC;Proctor EA;Zammitti C;Simms RW;Lauffenburger DA;Snyder-Cappione JE;Lafyatis R;Dooms H
免疫功能障碍是系统性硬化症（SSc）疾病过程的重要组成部分，但SSc中导致免疫细胞功能改变的机制仍不清楚。在这里，我们测量了来自SSc患者外周血的淋巴细胞亚群中共抑制受体（co-IR）PD-1、TIGIT、TIM-3和LAG-3的表达和功能。使用16色流式细胞术组分析免疫细胞亚群上的Co-IR表达水平。通过在存在共IR阻断抗体的情况下体外刺激PBMC后测量细胞因子产生来确定共IR的功能作用。将来自PBMC刺激培养物的上清液加入SSc成纤维细胞中，并测量其对成纤维细胞基因表达的影响。数学建模用于揭示SSc患者和健康对照者的co-IR功能之间的差异。与健康对照相比，在来自SSc患者的不同T细胞亚群中，共IR PD-1和TIGIT增加并共表达。TIM-3在SSc NK细胞中增加。PD-1、TIGIT和TIM-3抗体阻断揭示了在调节活化诱导的T细胞细胞因子产生中的患者特异性作用。与健康受试者相比，阻断TIGIT和TIM-3（而不是PD-1）未能逆转SSc患者中抑制的细胞因子产生，这表明SSc中存在增强的T细胞衰竭。最后，在抗TIM-3处理的PBMC培养物中分泌的细胞因子明显改变SSc成纤维细胞中的基因表达。SSc淋巴细胞中co-IR的表达和调节能力的改变可能通过调节炎症和/或纤维化部位的免疫细胞和成纤维细胞的烟碱介导的串扰而导致疾病病理生理学。
Immune dysfunction is an important component of the disease process underlying Systemic Sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. Here, we measured the expression and function of the co-inhibitory receptors (co-IRs) PD-1, TIGIT, TIM-3, and LAG-3 in lymphocyte subsets from the peripheral blood of SSc patients. Co-IR expression levels on immune cell subsets were analyzed using a 16-color flow cytometry panel. The functional role of co-IRs was determined by measuring cytokine production after in vitro stimulation of PBMCs in the presence of co-IR-blocking antibodies. Supernatants from PBMC stimulation cultures were added to SSc fibroblasts and their impact on fibroblast gene expression measured. Mathematical modeling was used to reveal differences between co-IR functions in SSc patients and healthy controls. The co-IRs PD-1 and TIGIT were increased, and co-expressed, in distinct T cell subsets from SSc patients, compared to healthy controls. TIM-3 was increased in SSc NK cells. PD-1, TIGIT and TIM-3 antibody blockade revealed patient-specific roles in modulating activation-induced T cell cytokine production. In contrast to healthy subjects, blocking TIGIT and TIM-3, but not PD-1, failed to reverse inhibited cytokine production in SSc patients, indicating the presence of enhanced T cell exhaustion in SSc. Finally, cytokines secreted in anti-TIM-3-treated PBMC cultures distinctly changed gene expression in SSc fibroblasts. Altered expression and regulatory capacity of co-IRs in SSc lymphocytes may contribute to disease pathophysiology by modulating the cytokine-mediated crosstalk of immune cells and fibroblasts at inflammatory and/or fibrotic sites.
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DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
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