提吉特
细胞生物学
受体
免疫受体
生物
抑制性突触后电位
免疫系统
CD8型
自身免疫
T细胞
免疫学
生物化学
神经科学
作者
Norio Chihara,Asaf Madi,Takaaki Kondo,Huiyuan Zhang,Nandini Acharya,Meromit Singer,Jackson Nyman,Nemanja D. Marjanovic,Monika S. Kowalczyk,Chao Wang,Sema Kurtuluş,Travis Law,Yasaman Etminan,James Nevin,Christopher D. Buckley,Patrick R. Burkett,Jason D. Buenrostro,Orit Rozenblatt-Rosen,Ana C. Anderson,Aviv Regev,Vijay K. Kuchroo
出处
期刊:Nature
[Springer Nature]
日期:2018-06-01
卷期号:558 (7710): 454-459
被引量:313
标识
DOI:10.1038/s41586-018-0206-z
摘要
The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4+ T cells promotes autoimmunity, whereas sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer1,2. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
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