Researchers have found a molecular link between the omega-3 polyunsaturated fatty acids (n-3 PUFA) and signaling involved in the T cell (T lymphocytes) maturation and differentiation. T lymphocytes such as CD4+ cells are the immune cells that circulate throughout the body and defend the host organism against foreign pathogens.
However, in some cases such as inflammatory bowel disease (an autoimmune disease), these immune cells are unable to differentiate between the foreign antigens (or foreign pathogens) from themselves. The inability to distinguish foreign particles from themselves leads to the self-activation that affects their normal function to defend against the foreign pathogens.
Before discussing different parts of the T cell signaling mediated by the omega-3 polyunsaturated fatty acids, I would like to discuss some of the most important things such as plasma membrane and its stability, phospholipids and omega-3 polyunsaturated fatty acids
Phospholipid bilayer structure of the plasma membranes
The cell membranes are composed of phospholipids bilayer and membrane proteins (such as integral and peripheral membrane proteins) that constitute the outer boundary of the cell. The cell membranes not only control the transport of biomolecules across the membrane but also regulate the cell to cell communication through signal transduction. The cell membrane also contributes to the fluidity and flexibility of the cell.
Cell membranes contain not only phospholipids as a major class of membrane lipids but also other membrane lipids such as glycolipids and sterols. It is the fatty acid residue that makes membrane lipids differ from each other even in the same class.
For example, each of the phospholipids can differ from each other based on the types of fatty acid residues present in the phospholipids. These fatty acid residues can be saturated or unsaturated or even polyunsaturated fatty acid residues and the same is true with glycolipids.
The lipid rafts of the plasma membrane and their stabilization
Plasma membranes have different lipid rafts (a small unit of the lipid bilayer) with different local concentrations of the membrane lipids. For example, lipid rafts in the apical plasma membrane contain more sphingolipids while lipid rafts in the basolateral plasma membrane contain more phosphatidylcholine.
Lipid rafts that contain significantly more sphingolipids and cholesterols with saturated fatty acid residues are found to be involved in the signal transduction. Lipid rafts can associate or dissociate from each other to regulate the formation of their phases in the plasma membrane.
However, the formation of lipid rafts can also be stabilized by the actin cytoskeleton. For example, monomeric G-actin is capable of polymerization leading to the formation of a complex of filamentous actin protein (F- actin) that participates in the organelle movement. Actin filaments interact with the integral proteins and form a bridge with the membrane lipid rafts. The interaction of actin filaments with integral proteins is mediated by a specific phospholipid also known as phosphatidylinositol-(4, 5)-bisphosphate.
What is phosphatidylinositol-(4, 5)-bisphosphate?
Phosphatidylinositol-(4, 5)-bisphosphate is one of the most important phospholipids involved in signal transduction. It contains diacylglycerol (DAG) and inositol-(1, 4, 5)-triphosphate (IP3) that upon hydrolysis play important roles in the downstream signaling. Phosphatidylinositol-(4, 5)-bisphosphate recruits the actin filament to the membrane lipid raft through the activation of actin-regulator proteins that promotes the polymerization of the G-actin.
Omega-3 polyunsaturated fatty acids
Polyunsaturated fatty acids are those unsaturated fatty acid residues that contain two or more carbon-carbon double bonds while omega-3 polyunsaturated fatty acids are those that have carbon-carbon double bonds on their third carbon atom from the end of the carbon chain.
Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) as shown in the figure at the top are some of the most important omega-3 polyunsaturated fatty acids found in fish oils. They are incorporated into the two major types of phospholipids; phosphatidylethanolamine and phosphatidylcholine. Lipid rafts containing phospholipids such as phosphatidylethanolamine and phosphatidylcholine are different from those lipid rafts containing sphingolipids and cholesterols in their fluidity.
Now, I will discuss how the signal transduction begins in the T cell and how it is affected by the omega-3 polyunsaturated fatty acids.
CD4+ T cell activation and downstream signaling
Antigenic peptide present on the Major Histocompatibility Complex II (MHCII) of the foreign pathogens binds to the CD4+ T cell receptor (TCR) causing reorientation of the lipid rafts on the T cell membranes that leads to the formation of Immunological Synapse (IS).
The formation of Immunological Synapse involves the changes in the lipid-lipid interaction that can be disrupted by the use of chemicals such as methyl-β-cyclodextrin and 7-ketocholesterols or n-3 PUFA such as EPA. And the disruption of lipid rafts results in the suppression of the T cell activation.
Immunological synapse interacts with downstream signaling molecules to form Central Supramolecular Activation Cluster (cSMAC) which further interacts with adhesion proteins to form the Peripheral Supramolecular Activation Cluster (pSMAC).
Once the antigenic peptide of the MHCII binds to the T cell receptors, tyrosine kinases located at the Immunological Synapse are activated that phosphorylates the adaptor protein LAT (Linker for the Activation of T cells). Phosphorylated LAT leads to the assembly of the signaling proteins to form a signalosome.
How omega-3 polyunsaturated fatty acids affect the activation of TCR?
Studies carried out using the immortalized Jurkat T cell line demonstrated that n-3 PUFAs displace many of the signaling proteins such as Src family kinases Lck, Fyn and LAT necessary for the T cell activation.
Therefore, both lipid-lipid interaction and lipid-protein interactions are important for the formation of Immunological Synapse. Omega-3 polyunsaturated fatty acids also interfere with the membrane-actin interaction by decreasing the level of the phosphatidylinositol-(4, 5)-bisphosphate in the CD4+ T cells that lead to the suppression of the actin cytoskeleton rearrangement.
Reference: European Journal of Pharmacology (Omega-3 fatty acids, lipid rafts, and T cell signaling)
Article DOI: 10.1016/j.ejphar.2015.03.091