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

• DOI: 10.1016/j.ebiom.2021.103734
• Publication Date: 2021-12-04T10:05:05Z
• Authors: Peter J. Siska; Jing Jiao; Carina Matos; Katrin Singer; Raffaela S. Berger; Katja Dettmer; Peter J. Oefner; Michelle D. Cully; Zhonglin Wang; William J. QuinnIII; Kristen N. Oliff; Benjamin J. Wilkins; Lanette M. Christ...; Liqing Wang; Wayne W. Hancock; Joseph A. Baur; Matthew H. Levine; Ines Ugele; Roman Mayr; Kathrin Renner; Liang Zhou; Marina Kreutz; Ulf H. Beier
• Keywords: Indoleamine 2,3-dioxygenase; Kynurenine pathway

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