Editorial: Fat chance to enhance B cell function

Plasma membranes are dynamic structures, and their lipid and fatty acid composition may be altered by several factors. They readily incorporate omega-3 fatty acids, including EPA and DHA [1]. The influence of EPA and DHA on the function of T cells, B cells, DCs, monocytes, macrophages, and neutrophils [2, 3] is believed to relate to modification of plasma membrane composition [1]. The fundamental mechanisms involved have traditionally been considered to be omega-3 fatty acid-induced changes in the physical state of the membrane (membrane “fluidity” or “order”) and changed availability of substrates for synthesis of immunoregulatory lipid mediators [1]. However, reported effects of omega-3 fatty acids on intracellular signaling cascades, for example, on the activation of PLC1, the generation of diacylglycerol, calcium influx, the activity of PKC and MAPKs, and cytokine gene expression in T cells [4], initiated studies on how these fatty acids influence the earliest stages of signal transduction in activated immune cells. These studies were given a focus by the development of the lipid raft model to describe membrane structure-function relationships and their dynamic nature. Whereas the concept of rafts has been much debated, studies using lipidomics and high-resolution imaging approaches have provided compelling evidence for their existence. Lipid rafts are regions of membranes with a distinct, characteristic structural composition [5]. They are believed to act as platforms to colocalise proteins involved in intracellular signaling pathways. The structural organization of the lipids within membranes impacts the way that membrane proteins are distributed. Rafts are particularly rich in sphingolipids and cholesterol, and the side-chains of the phospholipids present are usually highly enriched in saturated fatty acids compared with the surrounding nonraft regions of the membrane. As a result of the presence of cholesterol and saturated fatty acids, lipid rafts are more ordered (“less fluid”) than the surrounding (nonraft) portions of the membrane. Cytoplasmic proteins that are covalently modified by saturated fatty acids (palmitoyl or myristoyl moieties) and cell-surface proteins that are attached via a glycosyl phosphatidylinositol anchor are highly concentrated within lipid rafts. Many proteins involved in signal transduction, such as Src family kinases, G proteins, growth factor receptors, MAPKs, and PKC, are found predominantly in lipid rafts, which appear to act as signaling platforms by bringing together (i.e., colocalizing) the various signaling components, facilitating their interaction. The importance of rafts has been well demonstrated with respect to T-lymphocyte and B-lymphocyte responses to activation [6] (Fig. 1), and research over the last 10 years or so suggests that raft disruption underlies the mechanism of action of omega-3 fatty acids on T cells [7, 8]. The reason for this effect of omega-3 fatty acids, DHA in particular, has been believed to be because such highly unsaturated fatty acids have a poor affinity for cholesterol-rich regions of membranes and so, seem likely to be incorporated into nonraft regions of membranes, which subsequently perturbs the protein organization within the membrane, resulting in altered cell function. Gurzell et al. [9] report the effect of feeding SMAD3 / colitis-prone mice a DHA-rich diet, which also contained some EPA. This diet enhanced the EPA and DHA content of splenic B cells, diminished the clustering of rafts (induced with cholera toxin), and resulted in macroscopically larger (i.e., more dispersed) membrane raft regions. These membrane effects were associated with increased ex vivo secretion of inflammatory cytokines, expression of CD40, and increased in vivo B cell activation (MHCII and CD11c expression); Th2 cytokine concentrations in plasma; and cecal IgA concentration. The findings demonstrate that omega-3 fatty acids enhance B cell function and that this may be a result of modulation of structurefunction relationships within the plasma membrane. The enhancement of B cell function reported by Gurzell et al. [9] contrasts with the often-reported immunosuppressive effects of omega-3 fatty acids [1–3] but suggests that effects of these fatty acids on T and B cells might be different. The study of Gurzell et al. [9] is the latest in a line of publications by these authors. An in vitro study using the EL4 B cell line found that DHA, but not EPA, decreased raft clustering and that this was