Abstract
The differentiation and effector functions of both the innate and adaptive immune system are inextricably linked to cellular metabolism. The features of metabolism which affect both arms of the immune system include metabolic substrate availability, expression of enzymes, transport proteins, and transcription factors which control catabolism of these substrates, and the ability to perform anabolic metabolism. The control of lipid metabolism is central to the appropriate differentiation and functions of T lymphocytes, and ultimately to the maintenance of immune tolerance. This review will focus on the role of fatty acid (FA) metabolism in T cell differentiation, effector function, and survival. FAs are important sources of cellular energy, stored as triglycerides. They are also used as precursors to produce complex lipids such as cholesterol and membrane phospholipids. FA residues also become incorporated into hormones and signaling moieties. FAs signal via nuclear receptors and their channeling, between storage as triacyl glycerides or oxidation as fuel, may play a role in survival or death of the cell. In recent years, progress in the field of immunometabolism has highlighted diverse roles for FA metabolism in CD4 and CD8 T cell differentiation and function. This review will firstly describe the sensing and modulation of the environmental FAs and lipid intracellular signaling and will then explore the key role of lipid metabolism in regulating the balance between potentially damaging pro-inflammatory and anti-inflammatory regulatory responses. Finally the complex role of extracellular FAs in determining cell survival will be discussed.
Highlights
How Are Dietary Lipids Sensed by Cells, How Do They Signal?Free Fatty Acids (FFAs) Free fatty acids are defined as those not bound to albumin or esterified into larger molecules such as triglycerides (TGs) or phospholipids
In general saturated long-chain fatty acid (LCFA) can induce cytotoxicity whereas monounsaturated FAs are non-toxic or are cytoprotective to cells [101]. It has been shown in multiple cell types that addition of monounsaturated fatty acid (MUFA) to cells dose dependently protects against the cytotoxic effects of SFA by inhibiting FA synthesis and channeling FAs to TGs [100, 108,109,110,111]
Inhibition of PPARα in T cells was shown to skew the immune response, promoting IL-4 production and inhibiting IFN-γ. These results suggest that the PPARα agonist family of drugs might be repositioned for use in autoimmune diseases such as MS
Summary
Free Fatty Acids (FFAs) Free fatty acids are defined as those not bound to albumin or esterified into larger molecules such as triglycerides (TGs) or phospholipids. There are numerous binding proteins and receptors for FAs that enable them to remain soluble in the extracellular environment, signal at the plasma membrane, be transported within cells and enable promotion of transcription factor activity. Fatty Acid-Binding Proteins Once inside the cell FAs are bound by FABPs to increase their aqueous solubility in the cytoplasm and to chaperone them to Figure 2 | Fates of lipid within the cell.
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