气候变化领域集成服务门户(CCPortal): Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

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DOI	10.1073/PNAS.2103730118
	Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice
	Nakajima Y.; Chamoto K.; Oura T.; Honjo T.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:23
英文摘要	CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other agerelated diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism-related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1-deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Aging; Immunotherapy; One-carbon metabolism; PD-1; T cell subset
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238589
作者单位	Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University, Graduate School of Medicine, Kyoto, 606-8501, Japan
推荐引用方式 GB/T 7714	Nakajima Y.,Chamoto K.,Oura T.,et al. Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice[J],2021,118(23).
APA	Nakajima Y.,Chamoto K.,Oura T.,&Honjo T..(2021).Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice.Proceedings of the National Academy of Sciences of the United States of America,118(23).
MLA	Nakajima Y.,et al."Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice".Proceedings of the National Academy of Sciences of the United States of America 118.23(2021).