{"doi":"10.1016/j.ebiom.2021.103734","title":"Kynurenine induces T cell fat catabolism and has limited suppressive effects in vivo","abstract":"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 [ 13 C] 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 Lkynurenine. Mechanistically, [ 13 C]-tracing revealed that co-stimulated CD4 + T cells exposed to L-/D-kynurenine undergo increased b-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.","journal":"EBioMedicine","year":2021,"id":156616,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":54,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9668,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231748,"name":"Jing Jiao","orcid":"0000-0002-0018-1353","position":1,"is_corresponding":false},{"id":661761,"name":"Carina Matos","orcid":"0000-0002-1980-1380","position":2,"is_corresponding":false},{"id":662611,"name":"Katrin Singer","orcid":null,"position":3,"is_corresponding":false},{"id":661762,"name":"Raffaela S. Berger","orcid":"0000-0002-5783-3279","position":4,"is_corresponding":false},{"id":638801,"name":"Katja Dettmer","orcid":"0000-0001-7337-2380","position":5,"is_corresponding":false},{"id":49744,"name":"Peter J. Oefner","orcid":"0000-0002-1499-3977","position":6,"is_corresponding":false},{"id":231755,"name":"Michelle D. Cully","orcid":"0000-0002-3873-4929","position":7,"is_corresponding":false},{"id":65744,"name":"Zhong Lin Wang","orcid":"0000-0002-5530-0380","position":8,"is_corresponding":false},{"id":662612,"name":"William J. QuinnIII","orcid":null,"position":9,"is_corresponding":false},{"id":309768,"name":"Kristen N. Oliff","orcid":null,"position":10,"is_corresponding":false},{"id":314798,"name":"Benjamin J. Wilkins","orcid":"0000-0002-1797-7323","position":11,"is_corresponding":false},{"id":482048,"name":"Lanette M. Christensen","orcid":null,"position":12,"is_corresponding":false},{"id":231751,"name":"Liqing Wang","orcid":"0000-0001-7600-6992","position":13,"is_corresponding":false},{"id":231761,"name":"Wayne W. Hancock","orcid":"0000-0002-7211-5291","position":14,"is_corresponding":false},{"id":231765,"name":"Joseph A. Baur","orcid":"0000-0001-8262-6549","position":15,"is_corresponding":false},{"id":231763,"name":"Matthew H. 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