Dietary eicosapentaenoic acid modulates CTLA-4 expression in murine CD4+ T-cells.

We have demonstrated that downregulation of proliferation by CD4(+) T-cells in mice fed n-3 PUFA diets is dependent on the involvement of CD28. Therefore, we hypothesized that the balance of co-stimulatory and downregulatory properties of CD28 and CTLA-4, respectively, would be altered by diet. Mice were fed a control corn oil (CO)-enriched diet devoid of n-3 PUFA, or diets enriched with either docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) for 14d. The proliferation of splenic CD4(+) T-cells was suppressed by DHA and EPA following stimulation with anti-CD3 and anti-CD28. Surprisingly, the number of surface CD28 molecules was not reduced in activated CD4(+) T-cells from either group of n-3 PUFA-fed mice. However, in mice fed EPA, CTLA-4 protein levels were enhanced significantly 72 h post-activation (P<0.01). Therefore, we conclude that dietary EPA may suppress CD4(+) T-cell activation by enhancing the downregulatory co-receptor CTLA-4, while not altering the levels of CD28.

n-3 PUFA and membrane microdomains: a new frontier in bioactive lipid research.

In recent years, our understanding of the plasma membrane has changed considerably as our knowledge of lipid microdomains has expanded. Lipid microdomains include structures known as lipid rafts and caveolae, which are readily identified by their unique lipid constituents. Cholesterol, sphingolipids and phospholipids with saturated fatty acyl chain moieties are highly enriched in these lipid microdomains. Lipid rafts and caveolae have been shown to play an important role in the compartmentalization, modulation and integration of cell signaling. Therefore, these microdomains may have an influential role in human disease. Dietary n-3 polyunsaturated fatty acids (PUFA) ameliorate a number of human diseases including coronary heart disease, autoimmune and inflammatory disorders, diabetes, obesity and cancer, which has been generally linked to its membrane remodeling properties. Recent in vitro evidence suggests that perturbations in membrane composition alter the function of resident proteins and, consequently, cellular responses. This review examines the role of n-3 PUFA in modulating the lipid composition and functionality of lipid microdomains and its potential significance to human health.

Dietary n-3 polyunsaturated fatty acids promote activation-induced cell death in Th1-polarized murine CD4+ T-cells.

Dietary n-3 PUFAs have been shown to attenuate T-cell-mediated inflammation. To investigate whether dietary n-3 PUFAs promote activation-induced cell death (AICD) in CD4+ T-cells induced in vitro to a polarized T-helper1 (Th1) phenotype, C57BL/6 mice were fed diets containing either 5% corn oil (CO; n-6 PUFA control) or 4% fish oil (FO) plus 1% CO (n-3 PUFA) for 2 weeks. Splenic CD4+ T-cells were cultured with alpha-interleukin-4 (alphaIL-4), IL-12, and IL-2 for 2 days and then with recombinant (r) IL-12 and rIL-2 for 3 days in the presence of diet-matched homologous mouse serum (HMS) to prevent loss of cell membrane fatty acids, or with fetal bovine serum. After polarization, Th1 cells were reactivated and analyzed for interferon-gamma and IL-4 by intracellular cytokine staining and for apoptosis by Annexin V/propidium iodide. Dietary FO enhanced Th1 polarization by 49% (P = 0.0001) and AICD by 24% (P = 0.0001) only in cells cultured in the presence of HMS. FO enhancement of Th1 polarization and AICD after culture was associated with the maintenance of eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) in plasma membrane lipid rafts. In conclusion, n-3 PUFAs enhance the polarization and deletion of proinflammatory Th1 cells, possibly as a result of alterations in membrane microdomain fatty acid composition.

Effects of dietary n-3 polyunsaturated fatty acids on T-cell membrane composition and function.

Dietary n-3 PUFA have been shown to attenuate T-cell-mediated inflammation, in part, by suppressing T-cell activation and proliferation. n-3 PUFA have also been shown to promote apoptosis, another important mechanism for the prevention of chronic inflammation by maintaining T-cell homeostasis through the contraction of populations of activated T cells. Recent studies have specifically examined Fas death receptor-mediated activation-induced cell death (AICD), since it is the form of apoptosis associated with peripheral T-cell deletion involved in immunological tolerance and T-cell homeostasis. Data from our laboratory indicate that n-3 PUFA promote AICD in T helper 1 polarized cells, which are the mediators of chronic inflammation. Since Fas and components of the death-inducing signaling complex are recruited to plasma membrane microdomains (rafts), the effect of dietary n-3 PUFA on raft composition and resident protein localization has been the focus of recent investigations. Indeed, there is now compelling evidence that dietary n-3 PUFA are capable of modifying the composition of T-cell membrane microdomains (rafts). Because the lipids found in membrane microdomains actively participate in signal transduction pathways, these results support the hypothesis that dietary n-3 PUFA influence signaling complexes and modulate T-cell cytokinetics in vivo by altering T-cell raft composition.