Remodelling of primary human CD4⁺T cell plasma membrane order byn-3 PUFA

Abstract

Cell membrane fatty acids influence fundamental properties of the plasma membrane, including membrane fluidity, protein functionality, and lipid raft signalling. Evidence suggests that dietary n-3 PUFA may target the plasma membrane of immune cells by altering plasma membrane lipid dynamics, thereby regulating the attenuation of immune cell activation and suppression of inflammation. As lipid-based immunotherapy might be a promising new clinical strategy for the treatment of inflammatory disorders, we conducted in vitro and in vivo experiments to examine the effects of n-3 PUFA on CD4+ T cell membrane order, mitochondrial bioenergetics and lymphoproliferation. n-3 PUFA were incorporated into human primary CD4+ T cells phospholipids in vitro in a dose-dependent manner, resulting in a reduction in whole cell membrane order, oxidative phosphorylation and proliferation. At higher doses, n-3 PUFA induced unique phase separation in T cell-derived giant plasma membrane vesicles. Similarly, in a short-term human pilot study, supplementation of fish oil (4 g n-3 PUFA/d) for 6 weeks in healthy subjects significantly elevated EPA (20 : 5n-3) levels in CD4+ T cell membrane phospholipids, and reduced membrane lipid order. These results demonstrate that the dynamic reshaping of human CD4+ T cell plasma membrane organisation by n-3 PUFA may modulate down-stream clonal expansion.

Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance

“…Fish oil or n-3 PUFA intake has been shown to inhibit mitogen- or TCR activation-induced lymphocyte and CD4 + T cell proliferation, IL-2 production, and IL-2R expression, and also specific antigen-driven CD4 + T cell expansion under both ex vivo and in vivo conditions in animals (133–135), as well as the DTH skin response in humans (136). These T cell-inhibitory actions may be partly attributed to increased lipid peroxidation, modulation of membrane phospholipid composition, and cytoskeletal structure and disruption of lipid rafts (137–139). Changes in membrane lipid order are associated with alterations in T cell function (133, 140–142).…”

“…Changes in membrane lipid order are associated with alterations in T cell function (133, 140–142). Most recently, n-3 PUFA have been demonstrated to modulate T cell plasma membranes and oxidative phosphorylation and proliferation (139). The effect of n-3 PUFA on T cell function was also tested in fat-1 mice (137, 138), a transgenic mouse model that can endogenously synthesize n-3 PUFA, and the authors demonstrate that alteration in lipid raft formation was one potential mechanism by which n-3 PUFA suppresses T cell function.…”

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents

“…This is noteworthy, because the presence of long-chain n-3 PUFA in membrane phospholipids imparts unique biophysical properties which have been linked to alterations in plasma membrane structure and function [315–318]. DHA is known to influence membrane fluidity, ion permeability, fatty acid exchange, and resident protein function [319–321], including the inhibition of EGFR signaling in tumor-bearing mice by disassociating EGFR from lipid rafts [322]. Of particular interest is the ability of DHA to attenuate EGFR signaling.…”

n-3 Polyunsaturated Fatty Acids Impede the TCR Mobility and the TCR–pMHC Interaction of Anti-Viral CD8+ T Cells

“…The activation of CD4 + and CD8 + T cells was blunted after treatment with the n-3 PUFAs [3,13,[15][16][17][18][19][20]. Furthermore, the incorporation of the n-3 PUFAs into the membrane induces changes in membrane composition and microdomain organization [21,22] that may result in suppressed T cell functionality. However, the precise mechanism of how n-3 PUFAs influence T cell responses is unidentified.…”

“…Although TCR affinity cannot be altered by somatic hypermutation, membrane characteristics such as fluidity and lipid rafts can influence the degree of bond formation between the TCR and the pMHC [23][24][25]. Since n-3 PUFAs are known to affect membrane characteristics [21,22], the TCR-pMHC interaction may be regulated by n-3 PUFAs, which may subsequently influence CD8 + T cell functionality.…”