Tether before synapse

Tether before synapse C hemokines are captured on the surface of dendritic cells in lymph nodes, and they in turn capture T cells, say Rachel Friedman, Jordan Jacobelli, and Matthew Krummel (University of California, San Francisco, CA). The tethered T cells continue to search for a site worthy of a full immunological synapse, which they can form with either the same or another antigen-presenting cell (APC). Chemokines were known to costimulate T cell activation in vitro and up-regulate integrins that might slow down the T cells. But chemokines in solution also induced T cell migration past a surface laden with stimulatory T cell receptors (TCRs). This “paradox,” says Krummel, is resolved by the new data. He thinks the T cells bind APCs and then move arm over arm, “like swinging on monkey bars.” The San Francisco group found that T cells contacted, crawled along, and then attempted to crawl away from chemokine-laden APCs. For some time, however, they remained tethered to the APC due to chemokine-induced signaling in the T cell. The leading edge of these tethered cells projected out in search of an APC surface and was faster at forming an immunological synapse than if chemokine stimulation had never happened. The mechanism behind this improvement is unknown, but polarization of the T cell is probably involved, and the mechanism worked even if the eventual target APC did not itself have bound chemokines. “You used to think T cells were drawn into a cavity and once there they had to fend for themselves,” says Krummel. The new results “accentuate the idea of the microenvironment” in which T cell movements are tightly choreographed within the lymph node. Reference: Friedman, R.S., et al. 2006. Nat. Immunol. 7:1101–1108. Keeping valves c lear H eart valves achieve an impressive balancing act—they block large vessels but only temporarily. The blockage becomes more permanent in rheumatic valvular heart disease (VHD) when tiny, new blood vessels clog the valve. Now, Masatoyo Yoshioka, Keiichi Fukuda (Keio University, Tokyo, Japan), and colleagues fi nd that the antiangiogenic chondromodulin-I (Chm-I) normally keeps heart valves clear of new blood vessels, and its loss is associated with VHD. The fi nding was waiting to be made, says Fukuda, because “nobody was interested in studying this. Valvular heart disease is common, but most cardiologists think this is a disease for cardiac surgeons, and the surgeons only do operations.” Chm-I was already known as an antiangiogenic factor in avascular tissues of the eye and cartilage. The Tokyo group found that it was expressed in heart valves, and its deletion led to valves that were double the normal size and with almost 14-fold more capillaries. A similar pattern of Chm-I loss and new vessel growth was seen in mouse models of VHD and atherosclerosis. Mesenchymal cells from normal valves secreted Chm-I in vitro, and both this Chm-I and recombinant Chm-I had antiangiogenic activity. Valves may need constant protection against angiogenesis because they are under mechanical stress that could easily initiate the formation of new blood vessels. In some individuals this stress may compromise the mesenchymal cells, and thus begin the disease process that Fukuda hopes to combat with exogenous Chm-I. Reference: Yoshioka, M., et al. 2006. Nat. Med. doi:10.1038/nm1476. Fixing the hole M any bacteria attack cells using pore-forming toxins. An effl ux of K+ through these pores activates lipid synthesis that helps the cells survive, say Laure Gurcel, F. Gisou van der Goot (University of Geneva, Switzerland), and colleagues. The group’s fi rst clue was that treatment of cells with aerolysin, a pore-forming protein from Aeromonas, triggered processing of SREBP-2. Processed SREBP-2 enters the nucleus and induces transcription; its target genes turn on cholesterol and fatty acid biosynthesis. After testing many candidates for the source of the signal, the researchers added aerolysin in the presence of high K+ medium. With K+ effl ux prevented, the cells did not activate SREBP-2 and died in droves. A K+ ionophore, by contrast, was suffi cient to induce SREBP-2 activation. The pathway that emerged leads from K+ entry to assembly of two so-called infl ammasome complexes. These allow autoproteolysis of caspase-1, leading eventually to the activating proteolysis of SREBP-2, and the induction of SREBP-2 targets such as fatty acid synthase. All these steps were needed to promote cell survival after aerolysin treatment. The function of the lipid synthesis is uncertain, but a simple plugging of the hole is almost certainly not happening. “The pore we are looking at is extremely stable,” says van der Goot. “It’s not the surface occupied by the holes that requires synthesis.” Instead, repair may involve endocytosis or vesiculation. Either one may require lipid synthesis to drive or replenish the process. Reference: Gurcel, L., et al. 2006. Cell. 126:1135–1145.