Dietary tryptophan alters CD4+ T cell function in the lupus-prone B6. Sle1.Sle2.Sle3 (TC) mouse model

Abstract

Abstract Tryptophan (Trp) metabolism is altered in lupus patients with higher production of kynurenine (Kyn). We show that TC mice have the same alterations. To ascertain whether Trp plays a role in autoimmune pathogenesis, TC and B6 control mice were fed with either high or low Trp. High Trp exacerbated disease in TC mice while low Trp was protective. Expression of IDO1, the enzyme producing Kyn from Trp, was similar between TC and B6 mice, and its inhibition by 1MT did not change disease outcomes with and without dietary Trp variations. To identify the mechanism by which Trp plays a role in this process, we analyzed CD4 T cell phenotypes. Regulatory T cell (Treg) functional markers were altered by dietary Trp. Further, Tregs from TC mice consuming high Trp lost their suppressive capacity in vitro, whereas Tregs from TC mice on low Trp were as suppressive as that of B6 controls. Additionally, increasing Trp concentrations affected B6 and TC T cell polarization in vitro differently. A high Trp concentration increased the percentage of IFNg+ and FoxP3+ CD4+ T cells from B6 and TC mice under Th1 and Treg polarizing conditions, respectively. On the other hand, B6 Treg polarization increased with a higher Kyn concentration while TC Treg polarization decreased. These findings suggest that Trp and some of its metabolites modulate lupus pathogenesis in TC mice potentially by altering T cell phenotypes. Thus, these data emphasize a novel pro-inflammatory role for Trp metabolism in lupus. Supported by a grant from the NIH (RO1 AI143313) to LM.