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研究揭示CD4+ T细胞动态异质性对慢性感染的影响
作者:小柯机器人 发布时间:2021/11/22 15:10:50

加拿大大学健康网络玛格丽特公主癌症中心David G. Brooks、Laura M. Snell小组,报道了在慢性感染过程中一个由动态CD4+ T细胞异质性亚群造成的特异性抑制和阻断PD-L1诱导的功能恢复。相关论文于2021年11月18日发表于国际学术期刊《自然-免疫学》杂志。

研究人员发现PD-1:PD-L1在小鼠慢性感染期间特异性抑制CD4+ 辅助性T(TH)1细胞扩增,阻止CD4+ TH1细胞因子的产生并消除CD4+细胞毒性杀伤能力。抑制PD-L1可迅速恢复这些功能,同时放大和激活TH1样调节T细胞,并在系统范围内重新分配CD4-TH1细胞。这种效应与T细胞抗原受体信号传导减少相吻合,并将I型干扰素(IFN)信号传导网络重新导向了主要由IFN-γ介导的反应。从机制上讲,尽管PD-1表达很高,但PD-L1阻断剂特异性靶向具有预先确定且具有抑制增殖潜力的特定细胞,对最小循环TCF-1+滤泡辅助T细胞的影响有限。因此,CD4+ T细胞需要独特的分化和功能状态才能成为PD-L1特异性抑制靶点。

据悉,抑制PD-1:PD-L1信号已应用于临床免疫恢复。CD4+ T细胞在慢性感染和癌症中维持免疫力,但关于PD-1信号如何调节CD4TH细胞反应或通过检查点阻断恢复CD4+ TH介导的免疫知之甚少。

附:英文原文

Title: Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection

Author: Snell, Laura M., Xu, Wenxi, Abd-Rabbo, Diala, Boukhaled, Giselle, Guo, Mengdi, Macleod, Bethany L., Elsaesser, Heidi J., Hezaveh, Kebria, Alsahafi, Nirmin, Lukhele, Sabelo, Nejat, Sara, Prabhakaran, Ramanandan, Epelman, Slava, McGaha, Tracy L., Brooks, David G.

Issue&Volume: 2021-11-18

Abstract: Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4–TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.

DOI: 10.1038/s41590-021-01060-7

Source: https://www.nature.com/articles/s41590-021-01060-7

期刊信息

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:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex