CCR5 in 'stopgap' antiviral measure

After secondary respiratory virus infection, but before the generation of secondary memory CD8+ T cells, protective primary memory CD8+ T cells infiltrate mouse airways. In Immunity, Woodland and colleagues designate CCR5 as the chemokine receptor responsible for this transient protection. Two days after secondary virus infection, the number of primary memory CD8+ T cells and the concentration of CXCR3 and CCR5 chemokines increase in the airways. However, although abundant on the surface of primary memory CD8+ T cells, CXCR3 is dispensable for their airway recruitment after virus challenge. Presumably as a result of inflammatory cytokine production, CCR5 expression increases transiently on primary memory CD8+ T cells in secondary lymphoid organs of virus-challenged mice, and it is required for their trafficking to the airways. CCR5-deficient mice showed higher viral titers immediately after secondary virus infection. Unknown is whether CCR5 influences CD8+ T cell responses during other airway inflammatory disorders. CB

Immunity 29, 101–113 (2008)

Tat on the brain

The brain microvasculature differs from other vascular beds in the presence of 'tight' junctions that restrict permeability. Yet HIV can readily breach the 'blood-brain barrier' by disrupting these tight junctions. In the Journal of Neuroscience, Zhong et al. show that purified HIV-1 Tat protein induces cytoskeletal changes in cultured human brain microvascular endothelial cells by stimulating rapid caveolin-1 activation and signaling via Ras to downstream mediators. Tat exposure leads to downregulation of the transmembrane protein occludin and accessory proteins, zonula occludens ZO-1 and ZO-2, which are necessary for maintaining tight junctions. Inhibition of Ras signaling or knockdown of caveolin-1 abolish the Tat sensitivity. These data suggest circulating Tat can alter brain microvascular permeability, easing the barrier posed against HIV-1 and inflammatory cell passage into the brain. LAD

J. Neurosci. 28, 7788–7796 (2008)

Gatekeepers

Vascular endothelial-cadherin (VE-cad) transmembrane molecules contribute to barrier function at endothelial cell junctions. VE-cad surface expression is regulated by intracellular p120-catenin, but whether this interaction also influences leukocyte transmigration is not clear. In Blood, Alcaide et al. show that overexpression of p120-catenin inhibits leukocyte transmigration by preventing VE-cad displacement from the junctions, thereby preventing gaps through which leukocytes can migrate. Tyrosine phosphorylation of VE-cad, which occurs upon ICAM-1 engagement, is inversely correlated with p120-catenin abundance. Overexpression of p120-catenin blocks VE-cad phosphorylation and leukocyte transmigration, as does expression of a nonphosphorylatable VE-cad mutant. Contrary to previous hypotheses, VE-cad is not internalized at the gaps formed during transmigration, but rather lateral displacement seems to occur. These data suggest endothelial junctions are regulated by competition between p120-catenin and tyrosine kinases for interaction with VE-cad. LAD

Blood (18 July 2008) doi:10.1182/blood-2008-03-147181

Fractalkine-induced transmigration

Human endothelial cells can present antigen directly to CD4+ effector memory (EM) T cells to trigger proliferation and cytokine production in vitro as well as graft rejection in transplant settings. In the Journal of Immunology, Manes and Pober reveal differences between activated dermal microvascular and large vein endothelial cells in their ability to trigger transmigration of antigen-specific EM cells. TCR engagement under shear stress, mimicking blood flow, triggers formation of a 'finger-like' transendothelial protrusion before actual transmigration through the endothelial layer. Neither naive nor central memory CD4+ T cells form such protrusions, and they do not transmigrate under similar conditions. This process requires expression of ICAM-1 and the transmembrane chemokine CX3CL1, also known as fractalkine, which is recognized by CX3CR1, expressed only by the EM subset of CD4+ T cells. Further work is required to explore this diapedesis pathway. LAD

J. Immunol. 180, 8386–8392 (2008)

Sialylation in leukocyte arrest

Although post-translational glycosylation is required for selectin ligand and chemokine receptor function during leukocyte recruitment, specific glycosyltransferases required for leukocyte arrest are not well known. In Journal of Experimental Medicine, Sperandio and colleagues demonstrate that sialylation of the chemokine receptor CXCR2 by the glycosyltransferase ST3Gal-IV is essential for chemokine-triggered neutrophil arrest in vivo. Upon tumor necrosis factor stimulation, exteriorized cremaster muscle venules from ST3Gal-IV–deficient mice demonstrate defective L- and E-selectin–dependent leukocyte rolling, adhesion and extravasation after injection of the CXCR2 ligands CXCL1 or CXCL8. Carboxyfluorescein-labeled CXCR2 ligands bind much less to neutrophils from ST3Gal-IV–deficient mice or to wild-type mouse and human neutrophils treated with neuraminidase, which removes surface sialic acid. Microflow chamber assays show that ST3Gal-IV contributes to arrest of leukocytes in response to CXCL1. These data demonstrate the importance of ST3Gal-IV–dependent sialylation of CXCR2 in mediating leukocyte arrest during inflammation. DCB

J. Exp. Med. 205, 1435–1446 (2008)

gp130 cytokine tag team

Interleukin 6 (IL-6) suppresses neutrophil infiltration into acute inflammatory sites, thereby paving the way for a subsequent influx of mononuclear leukocytes. In the Journal of Immunology, Jones and co-workers show that the cytokine oncostatin M (OSM), although similar to IL-6 in its dependency on the gp130 signal transducer, suppresses mononuclear leukocyte infiltration. After intraperitoneal injection of Staphylococcus epidermidis supernatant, mice lacking OSMRβ—which forms a heterodimer with gp130 to transduce OSM signals—show increased numbers of infiltrating monocytes, but similar numbers of neutrophils, in the peritoneum. Compared to wild-type counterparts, S. epidermidis–challenged OSMRβ-deficient mice contain higher peritoneal concentrations of the chemokine CCL5—a factor established as capable of promoting monocyte recruitment—and show stronger peritoneal activation of NF-κB. Further work is needed to understand how IL-6 and OSM work cooperatively and/or antagonistically in situations of health and disease. CB

J. Immunol. 181, 2174–2180 (2008)

Written by Christine Borowski, Douglas C. Braaten & Laurie A. Dempsey