Monocarboxylate transporter MCT1 is a target for immunosuppression.
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.
Murray
Clare M
CM
Department of Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
Hutchinson
Raymond
R
Bantick
John R
JR
Belfield
Graham P
GP
Benjamin
Amanda D
AD
Brazma
Diana
D
Bundick
Robert V
RV
Cook
I David
ID
Craggs
Robert I
RI
Edwards
Susan
S
Evans
Leslie R
LR
Harrison
Richard
R
Holness
Elain
E
Jackson
Andrew P
AP
Jackson
Clive G
CG
Kingston
Lee P
LP
Perry
Matthew W D
MW
Ross
Andrew R J
AR
Rugman
Paul A
PA
Sidhu
Sasvinder S
SS
Sullivan
Michael
M
Taylor-Fishwick
David A
DA
Walker
P Craig
PC
Whitehead
Yvonne M
YM
Wilkinson
David J
DJ
Wright
Andrew
A
Donald
David K
DK
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
D007166:Immunosuppressive Agents; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D011994:Recombinant Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1