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Journal of Lipid Research, Vol. 50, 2377-2388, December 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Docosahexaenoic acid reduces suppressive and migratory functions of CD4CD25 regulatory T-cells

Akadiri Yessoufou^*,, Aude Plé^*, Kabirou Moutairou, Aziz Hichami^* and Naim Akhtar Khan^1,*

^* University of Burgundy, Unité Propre de Recherche de l'Enseignement Supérieur, Lipids and Cell Signaling, Faculty of Life Sciences, Dijon, France
Laboratory of Cell Biology and Physiology, Institut des Sciences Biomédicales et Appliquées and Faculty of Sciences and Techniques, University of Abomey-Calavi, Cotonou, Bénin

¹ To whom correspondence should be addressed. e-mail: naim.khan{at}u-bourgogne.fr

Immunological tolerance is one of the fundamental aspects of the immune system. The CD4⁺CD25⁺ regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4⁺CD25^– effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-β, and IL-10; nonetheless, this fatty acid increased the expression of p27^KIP1 mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease.

Supplementary key words extracellular signal-regulated kinase 1/2 • Smad7 • histone desacetylase 7

Abbreviations: AA, arachidonic acid; CFSE, carboxyfluorescien succinimidyl ester; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ERK, extracellular signal-regulated kinase; Foxp3, forkhead/winged helix transcription factor protein-3; HDAC, histone desacetylase; IL, interleukin; iTreg, inducible CD4⁺CD25⁺ regulatory T-cells; MDC, macrophage-derived chemokines; OD, optical density; PGE₂, prostaglandin E₂; PI3K, phosphatidylinositol-3-kinase; SDF-1, stroma cell-derived factor-1; Teff, CD4⁺CD25^– effector T-cells; TGF-β, transforming growth factor; Treg, CD4⁺CD25⁺ regulatory T-cells; TSA, trichostatin A

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