title: Monocarboxylate transporter MCT1 is a target for immunosuppression.
abstract: Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.
authors.affiliation: Department of Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Murray
authors.forename: Raymond
authors.initials: R
authors.lastname: Hutchinson
authors.forename: John R
authors.initials: JR
authors.lastname: Bantick
authors.forename: Graham P
authors.initials: GP
authors.lastname: Belfield
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Benjamin
authors.forename: Diana
authors.initials: D
authors.lastname: Brazma
authors.forename: Robert V
authors.initials: RV
authors.lastname: Bundick
authors.forename: I David
authors.initials: ID
authors.lastname: Cook
authors.forename: Robert I
authors.initials: RI
authors.lastname: Craggs
authors.forename: Susan
authors.initials: S
authors.lastname: Edwards
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Evans
authors.forename: Richard
authors.initials: R
authors.lastname: Harrison
authors.forename: Elain
authors.initials: E
authors.lastname: Holness
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Clive G
authors.initials: CG
authors.lastname: Jackson
authors.forename: Lee P
authors.initials: LP
authors.lastname: Kingston
authors.forename: Matthew W D
authors.initials: MW
authors.lastname: Perry
authors.forename: Andrew R J
authors.initials: AR
authors.lastname: Ross
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rugman
authors.forename: Sasvinder S
authors.initials: SS
authors.lastname: Sidhu
authors.forename: Michael
authors.initials: M
authors.lastname: Sullivan
authors.forename: David A
authors.initials: DA
authors.lastname: Taylor-Fishwick
authors.forename: P Craig
authors.initials: PC
authors.lastname: Walker
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Whitehead
authors.forename: David J
authors.initials: DJ
authors.lastname: Wilkinson
authors.forename: Andrew
authors.initials: A
authors.lastname: Wright
authors.forename: David K
authors.initials: DK
authors.lastname: Donald
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D066298:In Vitro Techniques; D007773:Lactates / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015394:Molecular Structure; D027501:Monocarboxylic Acid Transporters / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D027981:Symporters / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D007166:Immunosuppressive Agents; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D011994:Recombinant Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1