Journal Article10.1038/NSMB.3489
Dynamic regulation of CD28 conformation and signaling by charged lipids and ions.
Wei Yang,Wei Yang,Weiling Pan,S.H. Chen,Nicola Trendel,Shutan Jiang,Feng Xiao,Manman Xue,Wei Wu,Zeli Peng,Xiaoxi Li,Hongbin Ji,Xiaolong Liu,Hai Jiang,Haopeng Wang,Hongbin Shen,Omer Dushek,Hua Li,Chenqi Xu,Chenqi Xu +19 more
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TL;DR: The conformation and signaling of CD28 are regulated by two counteractive charged factors, acidic phospholipids and Ca2+ ions, which unravels a new regulatory mechanism for CD28 signaling and contributes to the understanding of the dependence of costimulation signaling on TCR signaling and the high sensitivity of T cells.
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Abstract: CD28 provides an essential costimulatory signal for T cell activation, and its function is critical in antitumor immunity. However, the molecular mechanism of CD28 transmembrane signaling remains elusive. Here we show that the conformation and signaling of CD28 are regulated by two counteractive charged factors, acidic phospholipids and Ca2+ ions. NMR spectroscopy analyses showed that acidic phospholipids can sequester CD28 signaling motifs within the membrane, thereby limiting CD28 basal signaling. T cell receptor (TCR) activation induced an increase in the local Ca2+ concentration around CD28, and Ca2+ directly disrupted CD28-lipid interaction, leading to opening and signaling of CD28. We observed that the TCR, Ca2+, and CD28 together form a dual-positive-feedback circuit that substantially amplifies T cell signaling and thus increases antigen sensitivity. This work unravels a new regulatory mechanism for CD28 signaling and thus contributes to the understanding of the dependence of costimulation signaling on TCR signaling and the high sensitivity of T cells.
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Mechanosensing through immunoreceptors.
TL;DR: The T cell antigen receptor is used as an example with which to review the current understanding of the mechanosensing properties of immunoreceptors and the forces that affect the ligand recognition, receptor triggering and signal transduction downstream of immunOREceptors, and their implication on lineage decision and effector function.
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Molecular and Cellular Functions of CTLA-4.
TL;DR: The role of costimulation in immune response induction as well as the main mechanisms by which CTLA-4 can inhibit this process are described.
156
Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell
Xinhai Zhu,Ke-Fang Li,Guichao Liu,Ruan Wu,Si-Yun Wang,Meng Xu,Ligong Lu,Peng Liu +7 more
TL;DR: The findings reveal that the metabolite butyrate of the gut microbiota facilitates the efficacy of anti-PD-1 immunotherapy by modulating TCR signaling of cytotoxic CD8 T cells, and is a highly promising therapeutic biomarker for enhancing antitumor immunity.
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Molecular mechanisms of T cell sensitivity to antigen.
TL;DR: This work reviews experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity, and organizes the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that promote TCR/pMHC binding, induce rapid TCR signaling, and amplify T CR signaling.
cis-B7:CD28 interactions at invaginated synaptic membranes provide CD28 co-stimulation and promote CD8+ T cell function and anti-tumor immunity.
Yunlong Zhao,Christine Caron,Calvin Lee,Xiaozheng Xu,Takeya Masubuchi,Chuan Wu,Jack D. Bui,Enfu Hui +7 more
TL;DR: In this paper , B7 ligands (CD80 and CD86) expressed by professional antigen-presenting cells (APCs) activate the main co-stimulatory receptor CD28 on T cells in trans.
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