小柯机器人

美国索尔克生物研究所Susan M. Kaech小组发现，β1-肾上腺素能受体将交感神经与T细胞衰竭联系起来。这一研究成果于2023年9月20日在线发表在国际学术期刊《自然》上。

研究人员通过β1-肾上腺素能受体ADRB1展示了应激相关儿茶酚胺与T细胞衰竭进展之间的新联系。研究人员发现，衰竭的CD8⁺ T细胞会增加ADRB1的表达，而ADRB1⁺ T细胞暴露于儿茶酚胺会抑制其细胞因子的产生和增殖。衰竭的CD8⁺ T细胞以ADRB1依赖性方式聚集在交感神经周围。β1-肾上腺素能信号的消减限制了慢性感染中T细胞向衰竭状态的发展，并在黑色素瘤中与免疫检查点阻断（ICB）结合使用时改善了效应子功能。在一个对ICB有抵抗力的胰腺癌模型中，β-受体阻滞剂和ICB协同作用，促进CD8⁺ T细胞反应，并诱导组织驻留记忆样T细胞的发育。恶性疾病与患者体内儿茶酚胺水平升高有关，这些研究结果证实了交感神经应激反应、组织神经支配和T细胞衰竭之间的联系。研究人员发现了一种新的机制：阻断CD8⁺ T细胞中的β-肾上腺素能信号可恢复抗肿瘤功能。

据介绍，CD8⁺ T细胞是针对病毒感染和肿瘤的免疫反应的重要组成部分，能够清除受感染的细胞和癌细胞。然而，当抗原无法被清除时，T细胞就会进入一种被称为衰竭的状态。虽然慢性抗原显然会导致CD8⁺ T细胞衰竭，但人们对组织中的应激反应如何调节T细胞功能却知之甚少。

附：英文原文

Title: The β1-adrenergic receptor links sympathetic nerves to Tcell exhaustion

Author: Globig, Anna-Maria, Zhao, Steven, Roginsky, Jessica, Maltez, Vivien I., Guiza, Juan, Avina-Ochoa, Natalia, Heeg, Maximilian, Araujo Hoffmann, Filipe, Chaudhary, Omkar, Wang, Jiawei, Senturk, Gokhan, Chen, Dan, OConnor, Carolyn, Pfaff, Samuel, Germain, Ronald N., Schalper, Kurt A., Emu, Brinda, Kaech, Susan M.

Issue&Volume: 2023-09-20

Abstract: CD8+ Tcells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, Tcells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ Tcell exhaustion, less is known about how stress responses in tissues regulate Tcell function. Here we show a new link between the stress-associated catecholamines and the progression of Tcell exhaustion through the β1-adrenergic receptor ADRB1. We identify that exhausted CD8+ Tcells increase ADRB1 expression and that exposure of ADRB1+ Tcells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8+ Tcells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of β1-adrenergic signalling limits the progression of Tcells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, β-blockers and ICB synergize to boost CD8+ Tcell responses and induce the development of tissue-resident memory-like Tcells. Malignant disease is associated with increased catecholamine levels in patients2,3, and our results establish a connection between the sympathetic stress response, tissue innervation and Tcell exhaustion. Here, we uncover a new mechanism by which blocking β-adrenergic signalling in CD8+ Tcells rejuvenates anti-tumour functions.

DOI: 10.1038/s41586-023-06568-6

Source: https://www.nature.com/articles/s41586-023-06568-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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