A new class of immunosuppressive compounds is shown to block T lymphocyte proliferation - the process by which white blood cells are activated during an immune response - by inhibiting lactate transport, as reported in the December 2005 issue of Nature Chemical Biology.
Proliferating T cells rely on energy from aerobic glycolysis, a process which generates ATP through the conversion of glucose to pyruvate or lactate. Clare Murray and colleagues have found that the immunosuppressive molecules function by inhibiting monocarboxylate transporter 1 (MCT1), a membrane protein involved in pumping lactate out of cells. Forcing intracellular lactate accumulation reduces the levels of glycolysis sufficiently to sap the energy required for rapid cellular growth, say the team.
Starting with compounds that showed potent inhibition of T cell proliferation in vitro and effective immunosuppression in vivo, Murray used proteomic methods to identify the target protein as MCT1. Consistent with MCT1 being the functional target, proliferating T cells had higher levels of MCT1 than resting cells did. These increased protein levels corresponded with increased lactate transport, which could be blocked by the inhibitory compounds, resulting in intracellular lactate accumulation and reduced glycolysis.
In addition to identifying a promising new target for developing immunosuppressants, these compounds will now provide a new tool for understanding MCT1 biology and the role of glycolysis in cell proliferation.
Clare Murray (AstraZeneca R&D Charnwood, UK)
Abstract available online.
(C) Nature Chemical Biology press release.
Message posted by: Trevor M. D'Souza