《细胞》：确定了生成记忆T细胞的代谢信号机制

编辑翻译：奇奇

译文校对：菁菁

文献在2021年2月最新的荷兰生物医学学术期刊《细胞》（Cell）首次刊登。文献中研究人员测定出了一种前所未知的生物机制，这种机制与免疫系统和T细胞有关，拓展了对免疫的认知。

美国圣犹达儿童研究医院(St.Jude Children's Research Hospital)的免疫学家已经测定出了一种前所未知的生物机制，这种机制就是免疫系统通过生成T细胞来杀死细菌、病毒和肿瘤细胞。

该发现对适应性免疫系统如何应对感染并产生记忆T细胞具有多重启示。实验揭示了抑制长寿命记忆T细胞发育的机制，这些记忆T细胞会随着时间不断更新以保护人体。用药理或遗传学方法阻断这些抑制机制可以增强针对感染和癌症的保护性免疫力。

研究人员还发现了记忆T细胞的一种亚型，他们将其命名为末端效应原细胞。测定出控制这些细胞的通路，可以提升通过操控该通路来增强免疫系统杀死微生物和癌细胞的能力的可能性。

测定控制通路也促进了认知，即饮食对免疫功能的影响可能比之前认为的更大。

这项研究由免疫学的池洪波博士领导，研究结果发表在《细胞》杂志上，第一作者是免疫学博士黄红玲和周培培。

CRISPR辅助测定代谢机制

当身体受到感染时，免疫系统开始产生效应T细胞来攻击入侵的细菌或病毒。这些T细胞有两种类型，一种类型是记忆前体细胞，它可以发育成记忆T细胞，这种记忆T细胞可以长期保护人体，这些是疫苗产生的T细胞；第二种是短寿命的末端效应T细胞，其具有直接的细胞毒活性。

在这项研究中，研究人员旨在确定 这一代谢机制，该机制可以控制免疫系统决定如何产生记忆T细胞。迟博士及其同事致力于抑制这种T细胞生成的鲜为人知的机制。

科学家使用一种称为CRISPR的基因操纵技术，筛选出小鼠细胞中的3000多种代谢控制基因，其目的是为了发现调节效应T细胞和记忆T细胞“命运”的基因。

营养物质在T细胞命运中起着意想不到的作用

该研究揭示了营养素（例如氨基酸和某些糖）在调节T细胞命运中所起的未知作用。令研究人员惊讶的是，该分析确定了抑制记忆T细胞产生的营养相关通路。

黄博士说：“关于营养素在免疫细胞功能中的作用，之前的观念是细胞依靠营养素作为能量来源和构成基础。但是我们的研究提供了另一种观点——营养素参与抑制通路，这种抑制也剥夺了可能有益于适应性免疫的某些营养素或代谢物。这似乎表明，饮食对免疫功能的影响可能要比之前所认知的更大。这也是今后研究的一个重要途径。”

确定新的T细胞亚型

研究还揭示了一种新的亚型效应T细胞，被命名末端效应原细胞。阻断这些细胞的发展可能是增强T细胞介质免疫力的关键。研究人员确定了一种通路，这种通路能控制T细胞从中间体向成熟末端效应原细胞过渡的转变。

研究人员发现，他们可以操纵该通路让末端效应原细胞保持在中间体阶段，这样可以诱导它们增殖，并产生更多的记忆T细胞。迟博士说：“这些发现突显了靶向该通路来增强针对感染和肿瘤保护性免疫的可能性。我们对这些发现感到非常兴奋。通过确定该营养信号中轴，我们的研究为增强记忆T细胞反应以及针对病原体和肿瘤的保护性免疫提供了新的生物学见解和治疗靶点。”

英语原文

Researchers Map Metabolic Signaling Machinery for Producing Memory T Cells

Immunologists at St. Jude Children's Research Hospital have mapped the previously unknown biological machinery by which the immune system generates T cells that kill bacteria, viruses and tumor cells.

The findings have multiple implications for how the adaptive immune system responds to infections to generate such memory T cells. The experiments revealed mechanisms that inhibit development of the long-lived memory T cells that continually renew to protect the body over time. Blocking these inhibitory mechanisms with pharmacological or genetic approaches could boost protective immunity against infection and cancers.

The researchers also discovered a subtype of memory T cells that they named terminal effector prime cells. Mapping the pathway that controls these cells raises the possibility of manipulating this pathway to enhance the ability of the immune system to kill microbes and cancer cells.

Mapping the control pathway also provided the insight that diet may have a greater influence on immune function than previously thought.

Led by Hongbo Chi, Ph.D., of the Department of Immunology, the research appears today in the journal Cell. The first authors are Hongling Huang, Ph.D., and Peipei Zhou, Ph.D., of Immunology.

CRISPR-assisted mapping of the metabolic machinery

When the body encounters an infection, the immune system begins to generate effector T cells to attack the invading bacteria or viruses. There are two types of these T cells. One type is the memory precursor cells, which can develop into memory T cells that persist long-term to protect the body. These are the T cells that vaccinations generate. The second type are short-lived terminal effector T cells, which have immediate cytotoxic activity.

In this study, researchers sought to map the metabolic machinery that controls how the immune system decides to produce memory T cells. Chi and his colleagues focused on the little-known mechanisms that inhibit the generation of this type of T cell.

The scientists used a gene-manipulating technology called CRISPR to sift through more than 3,000 metabolism-controlling genes in mouse cells. The goal was to discover genes that regulated the "fate" of effector T cells and memory T cells.

Nutrients play an unexpected role in T cell fate

The research revealed a previously unknown role that nutrients, such as amino acids and certain sugars, play in regulating T cell fate. To the investigators' surprise, the analysis identified nutrient-related pathways that suppressed memory T cell production.

"The preconceived notion about nutrients' role in immune cell function was that the cells rely on nutrients as an energy source and for building blocks," Huang said. "But our study provides another view—that nutrients are involved in inhibitory pathways, and that deprivation of certain nutrients or metabolites might be good for adaptive immunity.

"It seems to suggest that what you eat and drink may have a greater influence on immune function than previously appreciated," Huang said. "This will be an important pathway for future research."

New T cell subtype identified

The studies also revealed a new subtype of effector T cell, which they named terminal effector prime cells. Blocking development of these cells may be key to enhancing T cell-mediated immunity. The researchers' work identified a pathway that controls the transition of developing T cells from an intermediate stage to mature terminal effector prime cells.

The researchers found they could manipulate this pathway to keep terminal effector prime cells at this intermediate stage that would induce them to proliferate to produce more memory T cells. "These findings highlight the possibility of targeting this pathway to boost protective immunity against both infections and tumors," Chi said.

"We are extremely excited by these findings," Chi said. "By identifying this nutrient signaling axis, our studies provide new biological insights and therapeutic targets for enhancing memory T cell responses and protective immunity against pathogens and tumors."

参考文献：

HonglingHuang et al.In vivo CRISPR screening reveals nutrient signaling processesunderpinning CD8+ T cell fate decisions. Cell. February 25,2021DOI:doi.org/10.1016/j.cell.2021.02.021

本文内容由振东健康网整理发布