Dynamic regulation of CD28 conformation and signaling by charged lipids and ions
| Autor: | Haopeng Wang, Hua Li, Xiaolong Liu, Shutan Jiang, Zeli Peng, Wei Wu, Manman Xue, S.H. Chen, Xiaoxi Li, Chenqi Xu, Feng Xiao, Weiling Pan, Hai Jiang, Nicola Trendel, Omer Dushek, Hongbin Ji, Hongbin Shen, Wei Yang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Protein Conformation T cell T-Lymphocytes Receptors Antigen T-Cell chemical and pharmacologic phenomena Lymphocyte Activation Ion 03 medical and health sciences Mice Antigen CD28 Antigens Structural Biology Cell Line Tumor medicine Animals Molecular Biology Phospholipids Mice Knockout Chemistry T-cell receptor CD28 hemic and immune systems Nuclear magnetic resonance spectroscopy Cell biology Mice Inbred C57BL 030104 developmental biology Membrane medicine.anatomical_structure Calcium Function (biology) Signal Transduction |
| DOI: | 10.1038/nsmb.3489 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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