Immune regulation

Monocarboxylate transporter MCT1 is a target for immunosuppression. Murray, C. M. et al. Nature Chem. Biol. 30 Oct 2005 (doi:10.1038/nchembio744)

Previous studies identified a group of immunomodulatory compounds that were structurally distinct from other immunosuppressive agents. Murray et al. generated analogues of these compounds and showed that one inhibited T-cell proliferation in vivo. Surprisingly, whereas many immunosuppressive drugs (such as cyclosporin and rapamycin) inhibit T-cell cytokine production, this agent inhibited T-cell proliferation. Furthermore, its target was found to be monocarboxylate transporter 1 (MCT1), which is involved in the transport of monocarboxylates such as lactate and pyruvate across the plasma membrane. This agent could inhibit L-lactate efflux and thereby reduce the glycolytic rate of activated T cells, presumably (as the authors suggest) to rates that are insufficient to support rapid T-cell proliferation.

Immunological synapses

Cytotoxic granule polarization and cytolysis can occur without central supramolecular activation cluster formation in CD8+ effector T cells. O'Keefe, J. P. & Gajewski, T. F. J. Immunol. 175, 5581–5585 (2005)

Cell-surface receptors at the point of contact between an effector CD8+ T cell and a target cell segregate and cluster. Formation of a central supramolecular activation cluster (cSMAC) has been linked to granule exocytosis by, and cytotoxicity of, effector CD8+ T cells. However, data in this report indicate that formation of a cSMAC is not required. First, the number of effector CD8+ T cells that formed a cSMAC after encountering a target cell was fewer than the number of cells in which granules polarized towards the point of cell–cell contact. Second, the number of effector CD8+ T cells that formed a cSMAC was increased by target-cell expression of CD80, but the number of cells in which granules polarized towards the site of cell–cell contact and that mediated target-cell lysis was similar in the presence or absence of CD80.

Cytokines

Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression. Savignac, M. et al. EMBO J. 24, 3555–3564 (2005)

Savignac et al. show that downstream-regulatory-element antagonist modulator (DREAM), which is a transcriptional repressor that is released from DNA following Ca2+ signalling, is expressed by T cells and that its expression is downregulated after T-cell receptor (TCR) ligation. T cells isolated from transgenic mice expressing a dominant-active form of DREAM (which remains bound to DNA following Ca2+ signalling) showed decreased proliferation and cytokine production following TCR ligation. Conversely, when DREAM expression was decreased in wild-type splenocytes, an increase in the basal expression of mRNA encoding interleukin-2 (IL-2) and interferon-γ (IFN-γ) was detected. Because DREAM was bound to the promoters of the genes encoding IL-2 and IFN-γ, the authors suggest that DREAM has a role in regulating the basal expression of these cytokines.