Research ArticleInflammation

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

Science Translational Medicine  24 Aug 2016:
Vol. 8, Issue 353, pp. 353ra111
DOI: 10.1126/scitranslmed.aaf7483

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Naïve T cells nudged by lipid mediators

Specialized proresolving lipid mediators are known to modulate the innate immune system, and here, Chiurchiù et al. report that some of these lipid mediators can also inhibit human T cell activation. Incubation with lipid mediators increased naïve CD4+ T cell differentiation into regulatory T cells and suppressed differentiation of TH1 or TH17 cells. A mouse model that is unable to generate precursors for these lipid mediators also had an increase of TH1 and TH17 cells and relatively fewer regulatory T cells than wild-type mice. These results identify a potentially useful avenue of immunomodulation for steering T cell responses in inflammation or autoimmunity.

Abstract

Resolution of inflammation is a finely regulated process mediated by specialized proresolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)–derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series resolvins (resolvin D1 and resolvin D2) and maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8+ T cells and CD4+ T helper 1 (TH1) and TH17 cells but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4+ T cell differentiation into TH1 and TH17 by down-regulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3+ regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2−/−) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild-type mice. Additionally, either DHA supplementation in Elovl2−/− mice or in vivo administration of resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation.

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