Plasma membrane lipids play essential roles in regulating T cell signaling, differentiation, and effector functions. The major lipid species in the plasma membrane are glycerophospholipids, sphingolipids, and sterol lipids. TCR and costimulatory molecules lead to profound changes in the composition, distribution, and dynamic of plasma membrane lipids. For instance, cholesterol, sphingomyelin, and saturated phosphocholine are enriched at the contact zone between T cells and antigen-presenting cells during peptide/MHC complexes recognition, where they constitute a platform of lipid domains essential for optimal T cell signaling. Glycerophospholipid provide docking sites for binding pivotal signaling proteins as well as for their conformation, portioning, and mobility. Finally, plasma membrane lipids also act as second messengers with important immune-regulatory functions.

This Research Topic contains seven articles that review the current understanding of the mechanisms and molecules involved in the metabolism and function of membrane lipids and how differences in their content may affect T cell functional properties.

One of the main relevant discoveries in T cell biology has been the identification of specific signaling platforms enriched of cholesterol and glycosphingolipids, named lipid rafts, where critical enzymes, adaptors, and scaffold proteins are accumulated and trigger pivotal signaling pathways. After a nice historical revision of the biochemical, biophysical, and imaging approaches that have been exploited during the past 20 years for identifying the composition, dynamic, and functions of lipid rafts discuss the relevance of membrane rafts in T cell signaling functions and the pivotal role of CD28 costimulatory molecule in clustering membrane rafts at the immunological synapse (IS) through massive actin-reorganization events. Interestingly, cytoskeleton reorganization and actin polymerization are also regulated by phosphatidylinositol 4,5-biphosphate (PIP2), a membrane phospholipid that controls the activity of several proteins important for T cell functions. Phosphatidylinositol 4-phosphate 5-kinases (PIP5K) are mainly involved in PIP2 synthesis and, in human, three isoforms (α, β, and γ) and further splice variants have been identified. PIP5Kα and β have been recently identified as the main regulators of CD28 inflammatory and costimulatory functions (3–5), thus representing useful targets for inflammatory and autoimmune-based diseases. Using a recently discovered inhibitor of PIP5Kα, ISA-2011B evidenced a critical role of PIP5Kα in regulating CD28-mediated upregulation of inflammatory cytokines in type 1 diabetes patients.

Another important function of PIP2 is to serve as a substrate of class 1 phosphoinositide 3-kinases (PI3K) that, by phosphorylating PIP2 on the D3 position of the inositol ring, generates phosphatidylinositol 3,4,5-triphosphate (PIP3) lipids. The PI3K signaling pathway is crucial for the development, maturation, and functions of immune cells and, in their review, nicely discuss the role of PIP3 analogs, IP4 and IP7, and the enzymes responsible for their synthesis and turnover on stem cell homeostasis, neutrophil, and NK cell function as well as development and function of B cells and T cells. The pathological role of deregulated IP4 activity in lymphocytes is also discussed as well as its association with some B cell malignancies such as Kawasaki disease or severe combined immunodeficiency.

The maintenance of lipid raft structure and stability in T cells is also ensured by the amount of cholesterol, since changes in cholesterol content may affect the biophysical properties of lipid rafts.

You can submit your research work through online at https://bit.ly/3k7QUiv  

Media contact:

Christina

Editorial Assistant

Mail Id: cellsignaling@emedicalsci.com  

Journal of Cell Signaling.

Whatsapp number: + 1-504-608-2390