title: Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease.
abstract: T-cell activation requires increased ATP and biosynthesis to support proliferation and effector function. Most models of T-cell activation are based on in vitro culture systems and posit that aerobic glycolysis is employed to meet increased energetic and biosynthetic demands. By contrast, T cells activated in vivo by alloantigens in graft-versus-host disease (GVHD) increase mitochondrial oxygen consumption, fatty acid uptake, and oxidation, with small increases of glucose uptake and aerobic glycolysis. Here we show that these differences are not a consequence of alloactivation, because T cells activated in vitro either in a mixed lymphocyte reaction to the same alloantigens used in vivo or with agonistic anti-CD3/anti-CD28 antibodies increased aerobic glycolysis. Using targeted metabolic (13)C tracer fate associations, we elucidated the metabolic pathway(s) employed by alloreactive T cells in vivo that support this phenotype. We find that glutamine (Gln)-dependent tricarboxylic acid cycle anaplerosis is increased in alloreactive T cells and that Gln carbon contributes to ribose biosynthesis. Pharmacological modulation of oxidative phosphorylation rapidly reduces anaplerosis in alloreactive T cells and improves GVHD. On the basis of these data, we propose a model of T-cell metabolism that is relevant to activated lymphocytes in vivo, with implications for the discovery of new drugs for immune disorders.
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Gary D
authors.initials: GD
authors.lastname: Glick
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Wahl
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Charles
authors.initials: C
authors.lastname: Lesch
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Brian
authors.initials: B
authors.lastname: Sanchez
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Xikui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Ling-Yang
authors.initials: LY
authors.lastname: Hao
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Clarke
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Hurd
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Victor
authors.initials: V
authors.lastname: Tkachev
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Craig A
authors.initials: CA
authors.lastname: Byersdorfer
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
authors.forename: Laszlo
authors.initials: L
authors.lastname: Boros
authors.affiliation: Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.) tony@lycera.com.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002952:Citric Acid Cycle / Q000276:immunology; D005260:Female; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D010085:Oxidative Phosphorylation; D012266:Ribose / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D007519:Isoantigens; D005973:Glutamine; D012266:Ribose