Adding the LCFA lauric acid (a C12 fatty acid) to naive mouse T cells increased the differentiation of TH1 and TH17 cells by ~50% under TH cell-polarizing conditions and decreased the differentiation of regulatory T (TReg) cells by about one third. A similar positive effect of lauric acid on TH1 cell differentiation was observed in terms of interferon-γ production by CD4+ T cells from healthy human donors.
The effect of lauric acid on TH17 cell polarization was direct — not occurring through effects on dendritic cells — but did not seem to involve the candidate fatty acid receptors liver X receptor-α or various G protein-coupled receptors. In the absence of a defined receptor for lauric acid on T cells, the authors looked at the involvement of downstream signalling pathways. They showed that the most differentially expressed genes between lauric acid-treated and untreated TH17 cells include Maf and Mapk14 (which encodes p38). Lauric acid treatment of T cells under TH17 cell-polarizing conditions increased p38 phosphorylation, and pharmacological or genetic blockade of p38 inhibited the effect of lauric acid on TH17 cell differentiation. By contrast, the short-chain fatty acid (SCFA) propionate (C3) had a TReg cell-stimulating effect on mouse and human naive CD4+ T cells, which correlated with decreased p38 phosphorylation. The results suggest that the p38 MAPK pathway, which has well established roles in the response to environmental stress and in T cell differentiation, is a crucial mediator of the effects of fatty acids on T cells.
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