Monocarboxylate Transporter MCT1 Is a Target for Immunosuppression

Nat Chem Biol. 2005 Dec;1(7):371-6. doi: 10.1038/nchembio744.

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.

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Gene Expression Regulation
  • Graft vs Host Disease / immunology
  • Humans
  • Immunosuppressive Agents / immunology
  • Immunosuppressive Agents / pharmacology*
  • In Vitro Techniques
  • Lactates / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Molecular Structure
  • Monocarboxylic Acid Transporters / drug effects*
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / immunology
  • Rats
  • Rats, Inbred Lew
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Symporters / drug effects*
  • Symporters / genetics
  • Symporters / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Time Factors

Substances

  • Immunosuppressive Agents
  • Lactates
  • Monocarboxylic Acid Transporters
  • Recombinant Proteins
  • Symporters
  • monocarboxylate transport protein 1