Polyunsaturated fatty acids interfere with formation of the immunological synapse.
Polyunsaturated fatty acids (PUFAs) exert inhibitory effects on T cell-mediated immune responses. Activation of T cells in vivo depends on formation of an immunological synapse (IS) at the T cell/antigen-presenting cell (APC) interface. Here, we analyzed effects of PUFA treatment on the formation of the IS and APC-induced human T cell activation. In T cells treated with the PUFA eicosapentaenoic (EPA; 20:5,n-3) and arachidonic acid (20:4,n-6), stimulated by superantigen-presenting cells or APCs, relocalization to the IS of distinct molecules [F-actin, talin, leukocyte functional antigen-1alpha, clusters of differentiation (CD)3epsilon] was inhibited markedly compared with cells treated with saturated fatty acid, whereas relocalization of protein kinase Ctheta to the IS remained unaffected. CD3-induced, sustained phosphorylation of nucleotide exchange factor Vav, which controls cytoskeletal rearrangements underlying IS formation, was significantly reduced in EPA-treated Jurkat and peripheral blood T cells. In addition, T cell raft disruption by methyl-beta-cyclodextrin treatment and experiments with a chimeric linker for activation of T cell proteins, which is resistant to PUFA effects on lipid rafts, revealed modifications of lipid rafts as a crucial factor for PUFA-mediated inhibition of APC-stimulated cytoskeletal rearrangements. Furthermore, the efficiency of T cell/APC conjugate formation was significantly reduced with EPA-treated T cells, as was stimulation of CD69 expression, which is not altered following antibody-mediated T cell activation. In conclusion, PUFA treatment of T cells qualitatively and quantitatively alters IS formation, thereby extending T cell signaling defects to pathways that are not intrinsically altered in PUFA-treated T cells when stimulated by antibodies.
Geyeregger
René
R
Department of Internal Medicine, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Zeyda
Maximilian
M
Zlabinger
Gerhard J
GJ
Waldhäusl
Werner
W
Stulnig
Thomas M
TM
D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D016718:Arachidonic Acid / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects* / Q000276:immunology; D018797:Cell Cycle Proteins / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000276:immunology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology; D019169:Jurkat Cells; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D021962:Membrane Microdomains / Q000187:drug effects; D010766:Phosphorylation; D011493:Protein Kinase C / Q000276:immunology; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav; D016028:Receptors, Leukocyte-Adhesion / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D047392:beta-Cyclodextrins / Q000494:pharmacology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016718:Arachidonic Acid; D017252:CD3 Complex; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D015118:Eicosapentaenoic Acid; D007527:Isoenzymes; D037181:Lectins, C-Type; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D016028:Receptors, Leukocyte-Adhesion; D047392:beta-Cyclodextrins; D000099192:CD69 Antigens; C496618:VAV1 protein, human; C108732:methyl-beta-cyclodextrin; C076233:PRKCQ protein, human