Kynurenine induces T cell fat catabolism and has limited suppressive effects in vivo

Background: L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine. Methods: L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using [C-13] glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice. Findings: We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, [C-13]-tracing revealed that co-stimulated CD4(+) T cells exposed to L-/D-kynurenine undergo increased beta-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 mM, which is close to human kidney (6 mM) and head and neck cancer (14 mM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1(-/-) mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection. Interpretation: Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials. (C) 2021 The Author(s). Published by Elsevier B.V.

Automated summary

The study evaluated D-kynurenine as an immunosuppressive therapeutic with potential to produce fewer neurotoxic metabolites compared to L-kynurenine. Results showed that D-kynurenine inhibited T cell proliferation and protected mice from autoimmune colitis, but did not attenuate more stringent immunological challenges like antigen mismatched cardiac allograft rejection.