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)1, 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.
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Acknowledgements
We thank A. Baines for helpful advice on protein purification from red blood cells and K. Wood, D. Cantrell and A. Halestrap for helpful advice and discussions. We thank K. Jolley for technical assistance in analyzing glucose metabolites by GC-MS, E. Newboult and S. Cartlidge for tumor cell proliferation studies and M. Erlansson and L. Jansson for the CIA model. We gratefully acknowledge the assistance of S. Guile and R. Mohammed in collating the chemical synthesis and analysis information.
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Supplementary information
Supplementary Fig. 1
Effects of novel immunomodulators on in vitro human T-lymphocyte responses. (PDF 178 kb)
Supplementary Fig. 2
Effect of MCT1 inhibitors on the intracellular pH of human T-lymphocytes. (PDF 22 kb)
Supplementary Table 1
Chemical structures and names. (PDF 10 kb)
Supplementary Table 2
Effect of compound 1 on proliferation of human cells. (PDF 19 kb)
Supplementary Table 3
Correlation between compound binding to Jurkat T-cells and MCT1 and inhibition of PBMC proliferation. (PDF 20 kb)
Supplementary Table 4
Correlation between compound effects on lactate levels, DNA synthesis and inhibition of proliferation in human T-cells. (PDF 19 kb)
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Murray, C., Hutchinson, R., Bantick, J. et al. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat Chem Biol 1, 371–376 (2005). https://doi.org/10.1038/nchembio744
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DOI: https://doi.org/10.1038/nchembio744
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