Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice
Josephine Brown,
Georges Abboud,
Longhuan Ma,
Seung-Chul Choi,
Nathalie Kanda,
Leilani Zeumer-Spataro,
Jean Lee,
Weidan Peng,
Joy Cagmat,
Tamas Faludi,
Mansour Mohamadzadeh,
Timothy Garrett,
Laura Mandik-Nayak,
Alexander Chervonsky,
Andras Perl,
Laurence Morel
Affiliations
Josephine Brown
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Georges Abboud
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Longhuan Ma
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Seung-Chul Choi
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Nathalie Kanda
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Leilani Zeumer-Spataro
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Jean Lee
Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA
Weidan Peng
Lankenau Institute for Medical Research, Wynnewood, PA, USA
Joy Cagmat
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Tamas Faludi
Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY 13210, USA
Mansour Mohamadzadeh
Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Timothy Garrett
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Laura Mandik-Nayak
Lankenau Institute for Medical Research, Wynnewood, PA, USA
Alexander Chervonsky
Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA
Andras Perl
Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY 13210, USA
Laurence Morel
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; Corresponding author
Summary: A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus T cells processed tryptophan differently, suggesting a contribution of T cell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased T cell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and T cell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus T cells.
