Docosahexaenoic acid reduces suppressive and migratory functions of CD4+CD25+ regulatory T-cells.
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-beta, 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.
Yessoufou
Akadiri
A
University of Burgundy, Unité Propre de Recherche de l'Enseignement Supérieur, Lipids and Cell Signaling, Faculty of Life Sciences, Dijon, France.
Plé
Aude
A
Moutairou
Kabirou
K
Hichami
Aziz
A
Khan
Naim Akhtar
NA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D060908:CTLA-4 Antigen; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D054398:Receptors, CCR4 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C514936:CXCR4 protein, mouse; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D004281:Docosahexaenoic Acids