Nectins and Nectin-like molecules (Necls) play a critical role in cell polarity within epithelia and in the nervous and reproductive systems. Recently, immune receptors specific for Nectins/Necls have been described. Since expression and distribution of Nectins/Necls is often subverted during tumorigenesis, it has been suggested that the immune system may use these receptors to recognize and eliminate tumors. Here we describe a novel immunoreceptor, WUCAM, which is expressed on human follicular B helper T cells (Tfh) and binds a Nectin/Necl family member, the poliovirus receptor (PVR), under both static and flow conditions. Futhermore, we demonstrate that PVR is abundantly expressed by follicular dendritic cells (FDC) within the germinal center. These results reveal a novel molecular interaction that mediates adhesion of Tfh to FDC and provide the first evidence that immune receptors for Nectins/Necls may be involved the generation of T cell-dependent antibody responses.
The phosphoinositide 3-kinase (PI3K) catalytic subunit p110␦ is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractantdirected migration. We report here that p110␦ is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor ␣ (TNF␣). Specifically, administration of the selective inhibitor of PI3K␦, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110␦. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3K␦ in TNF␣-induced signaling is demonstrated by a reduction in Aktphosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110␦ expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3K␦ may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium. (Blood.
Humoral immunity to viruses and encapsulated bacteria is comprised of T cell–independent type 2 (TI-2) antibody responses that are characterized by rapid antibody production by marginal zone and B1 B cells. We demonstrate that toll-like receptor (TLR) ligands influence the TI-2 antibody response not only by enhancing the overall magnitude but also by skewing this response to one that is dominated by IgG isotypes. Importantly, TLR ligands facilitate this response by inducing type I interferon (IFN), which in turn elicits rapid and significant amounts of antigen-specific IgG2c predominantly from FO (follicular) B cells. Furthermore, we show that although the IgG2c antibody response requires B cell–autonomous IFN-α receptor signaling, it is independent of B cell–intrinsic TLR signaling. Thus, innate signals have the capacity to enhance TI-2 antibody responses by promoting participation of FO B cells, which then elaborate effective IgG anti-pathogen antibodies.
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