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调节性髓系细胞通过代谢物丙酮醛的细胞间转移使T细胞失活
2020-04-27 13:32
来源：小柯机器人

德国慕尼黑工业大学Bastian Höchst、Percy A. Knolle等研究人员合作发现，调节性髓系细胞通过代谢物丙酮醛的细胞间转移使T细胞失活。相关论文于2020年4月23日发表在《自然—免疫学》上。

研究人员发现，人类髓系来源抑制细胞（MDSC）的特点是代谢大大降低，并将这种受损的代谢状态赋予CD8+T细胞，从而使其效应器功能瘫痪。研究人员鉴定到由氨基脲敏感的胺氧化酶产生的二羰基自由基丙酮醛的积累，从而引起MDSC的代谢表型和MDSC介导的CD8+T细胞失活。
 
在鼠类癌症模型中，二羰基活性的中和作用克服了MDSC介导的T细胞抑制作用，并与检查点抑制作用一起改善了癌症免疫疗法的功效。
 
因此，这些研究结果将二羰基自由基丙酮醛鉴定为MDSC的标志代谢产物，其介导T细胞失活并且可以作为改善癌症免疫疗法的靶标。
 
据介绍，调节性髓系免疫细胞（例如，MDSC）在发炎或癌变的组织中聚集并阻断免疫细胞效应子的功能。人们缺乏对MDSC抑制活性的机制了解以及用于鉴定它们的标记物，因此阻碍了克服T细胞抑制和释放抗癌免疫力的研究。
 
附：英文原文

Title: Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal

Author: Tobias Baumann, Andreas Dunkel, Christian Schmid, Sabine Schmitt, Michael Hiltensperger, Kerstin Lohr, Vibor Laketa, Sainitin Donakonda, Uwe Ahting, Bettina Lorenz-Depiereux, Jan E. Heil, Johann Schredelseker, Luca Simeoni, Caroline Fecher, Nina Krber, Tanja Bauer, Norbert Hser, Daniel Hartmann, Melanie Laschinger, Kilian Eyerich, Stefanie Eyerich, Martina Anton, Matthew Streeter, Tina Wang, Burkhart Schraven, David Spiegel, Farhah Assaad, Thomas Misgeld, Hans Zischka, Peter J. Murray, Annkristin Heine, Mathias Heikenwlder, Thomas Korn, Corinna Dawid, Thomas Hofmann, Percy A. Knolle, Bastian Hchst

Issue&Volume: 2020-04-23

Abstract: Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.

DOI: 10.1038/s41590-020-0666-9

Source: https://www.nature.com/articles/s41590-020-0666-9

Nature Immunology：《自然—免疫学》，创刊于2000年。隶属于施普林格·自然出版集团，最新IF：31.25
官方网址：https://www.nature.com/ni/
投稿链接：https://mts-ni.nature.com/cgi-bin/main.plex


本期文章：《自然—免疫学》：Online/在线发表

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