Background:
Microbial metabolism of dietary tryptophan generates a wide range of indoles, which are important signaling molecules in microbial communities, as well as in host-microbial cross-talk, and may contribute to intestinal and systemic immune homeostasis. Recently we demonstrated that serum levels of these indoles correlated with COVID-19 disease severity and circulating cytokine levels. However, the direct effects of these indoles on T cell function has not been thoroughly examined.
Aim:
To investigate the impact of bacterial-derived tryptophan metabolites on human lymphocyte polarization and differentiation.
Methods:
Following Naïve CD4+ T cell sorting from human peripheral blood mononuclear cells (PBMC), we stimulated lymphocytes with CD3&CD28 agonists to promote effector T cells differentiation and quantified cytokine secretion (IL-5, IL-13, IFN-γ, IL-10, IL-17, and IL-22) after 72h stimulation. Cell polarization was examined by flow cytometry and ELISA.
Results:
Following CD3&CD28 stimulation, Indole-3-acrylic acid (IA) and Indole-3-pyruvate (IPYA) significantly reduced secretion of IL-5 and IL-13 in a dose dependent manner; IPYA, IET, and Indoxyl 3-sulfate (I3S) have a stronger effect on IFN-gamma secretion than the other indoles; In contrast, IL-10 secretion was increased following exposure to many of the indoles. Tryptamine, IA, and Indole-3- glyoxylic acid (IGoxA) reduced IL17 secretion, while many indoles promoted IL22 secretion.
Conclusion:
Microbial-derived indoles have distinct effects on cytokine secretion from activated lymphocytes, but the pattern is not correlated with the aryl hydrocarbon receptor (AhR) activation, which suggest other signaling mechanisms also play a role.
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