Key Points
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Lipid molecules are extremely diverse, but their functions are poorly understood. Different lipid species are co-regulated in immune cells.
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Lipids have heterogeneous distributions in the membrane bilayer, and they form various lipid domains to provide platforms for local signalling.
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Different T cell subsets have distinct membrane lipid compositions, which are crucial for their physiological functions.
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Membrane lipids have sophisticated roles in regulating T cell signalling — such as formation of the immune synapse, recruitment of cytosolic signalling proteins, safety control of immunoreceptors, mediating protein island formation and regulating the conformation, partitioning and mobility of membrane proteins. A single lipid molecule can have multiple regulatory functions.
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Modulating membrane lipid composition of T cells can be applied to treat cancers and autoimmune diseases. Cellular lipid metabolic pathways have 'metabolic checkpoints' that are good drug targets for immunotherapies.
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More mechanistic studies on membrane lipids are needed to pave the way for the development of new generation of lipid-based immunotherapies.
Abstract
The plasma membrane is an essential cellular structure that separates the cell interior from the extracellular environment, while allowing for the exchange of signals and materials that are essential for cell survival and function. The complexity of the lipids in the plasma membrane has been long appreciated, but recent developments in lipidomics and imaging technologies have improved our understanding of plasma membrane lipid dynamics. New studies have started to unveil important functions for plasma membrane lipids in regulating T cell signalling. Importantly, it has been shown that the modulation of membrane lipids can be used to harness T cell activity to treat cancer and autoimmunity. Therefore, lipid-based immunotherapy might be a promising new clinical strategy.
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Change history
12 February 2018
In the main text of this Review article, ACAT1 was incorrectly defined as 'acetyl-CoA acetyltransferase, mitochondrial'. The correct definition of ACAT1 in this article is 'acyl-CoA cholesterol acyltransferase 1'. Nature Reviews Immunology apologize for this error, which has now been corrected in the PDF and HTML versions of the article.
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Acknowledgements
C.X. is funded by CAS Strategic Priority Research Program XDB08020100, NSFC (31370860, 31425009 and 31530022) and MOST (2012CB910804). The authors thank C. Yan and J. Guo for their assistance in the preparation of this manuscript. We apologize to the many scientists whose work could not be included into this review owing to space limitations.
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Glossary
- Lipid raft model
-
The lipid raft model was initially developed to describe the membrane domains that are resistant to cold detergent extraction or mechanical disruption. Now, lipid rafts are viewed as dynamic nanoscale assemblies of sphingolipids, cholesterol and proteins that support local membrane signalling and trafficking.
- Free diffusion mode
-
Molecules diffuse freely in Brownian motion.
- Trapped diffusion mode
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Molecules do not diffuse freely but can be transiently trapped into domains of higher molecular order when interacting with immobilized or slow moving entities.
- Ferroptosis
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A non-apoptotic form of cell death that is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids.
- Palmitoylation sites
-
Cysteine sites for reversible post-translational addition of palmitic acid to the sulfhydryl group to form a thioester. Palmitoylation regulates protein trafficking, sorting, clustering, stability and aggregation.
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Wu, W., Shi, X. & Xu, C. Regulation of T cell signalling by membrane lipids. Nat Rev Immunol 16, 690–701 (2016). https://doi.org/10.1038/nri.2016.103
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DOI: https://doi.org/10.1038/nri.2016.103
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