p53 keeps bystanders at the gates.

The inappropriate expansion of self-reactive "bystander" T cells can contribute to autoimmune disease. In this issue of Immunity, Watanabe et al. (2014) demonstrate that the tumor suppressor p53 prevents the cytokine-dependent proliferation of T cells in the absence of cognate antigens.

Vav2 lacks Ca2+ entry-promoting scaffolding functions unique to Vav1 and inhibits T cell activation via Cdc42.

Vav family guanine nucleotide exchange factors (GEFs) are essential regulators of immune function. Despite their structural similarity, Vav1 promotes and Vav2 opposes T cell receptor (TCR)-induced Ca2+ entry. By using a Vav1-deficient Jurkat T cell line, we find that Vav1 facilitates Ca2+ entry via non-catalytic scaffolding functions that are encoded by the catalytic core of Vav1 and flanking linker regions. We implicate, in this scaffolding function, a previously undescribed polybasic motif that is strictly conserved in Vav1 and absent from Vav2 in tetrapods. Conversely, the catalytic activity of Vav2 contributes to the suppression of TCR-mediated Ca2+ entry. By performing an in vivo 'GEF trapping' assay in intact cells, we demonstrate that Cdc42 interacts with the catalytic surface of Vav2 but not Vav1, and that Vav1 discriminates Cdc42 from Rac1 via F56 (W56 in Rac1). Finally, the Cdc42-specific inhibitor ZCL278 and the shRNA-mediated suppression of Cdc42 each prevent the inhibition of TCR-induced Ca2+ entry by Vav2. These findings define stark differences in the functions of Vav1 and Vav2, and provide an explanation for the differential usage of these Vav isoforms by immune subpopulations.

Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of antinucleic acid autoantibodies, high levels of circulating type I interferon (IFN-I), and an IFN-I-dependent elevated expression of activating FcγR. Increases in neutrophils and monocytes are often observed in clinical SLE, but how these contribute to autoantibody and IFN-I production is poorly understood. Here, we analyzed SLE pathogenesis in 564Igi mice, an SLE-model strain carrying gene-targeted heavy and light chain antibody genes encoding an anti-RNA autoantibody in a C57BL/6 background. Similar to human SLE patients, 564Igi mice produce anti-RNA autoantibodies and expanded neutrophil and monocyte populations. These myeloid cells produced IFN-I and exhibit increased FcγRIV expression induced via an IFN-I autocrine loop. A direct effect of IFN-I on 56 Igi BM B cells and neutrophils was supported by their upregulation of "IFN-I signature genes". In addition, 564Igi developing B cells showed upregulated TLR7 resulting in IgG2a/2b class switch recombination and autoantibody production. Our results indicate that the production of anti-RNA autoantibody is sufficient to induce an increase of BM, blood, and spleen IFN-I-producing neutrophils, and suggest a mechanism by which autoantibody and IFN-I contribute to SLE by activating B lymphocytes, neutrophils, and monocyte effector cells in vivo.

Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3{beta} inhibition.

The mechanism by which regulatory T (Treg) cells suppress the immune response is not well defined. A recent study has shown that ß-catenin prolongs Treg cell survival. Because ß-catenin is regulated by glycogen synthase kinase 3ß (GSK-3ß)-directed phosphorylation, we focused on GSK-3ß and the role it plays in Treg cell function. Inhibition of GSK-3ß led to increased suppression activity by Treg cells. Inhibitor-treated Treg cells exhibited prolonged FoxP3 expression and increased levels of ß-catenin and of the antiapoptotic protein Bcl-xL. Systemic administration of GSK-3ß inhibitor resulted in prolonged islet survival in an allotransplant mouse model. Our data suggest that GSK-3ß could be a useful target in developing strategies designed to increase the stability and function of Treg cells for inducing allotransplant tolerance or treating autoimmune conditions.

Dendritic cell maturation occurs through the inhibition of GSK-3ß.

Dendritic cell (DC) maturation results in changes in antigen processing and presentation, governing the fate of adaptive immunity. Understanding the intracellular signaling pathways governing DC maturation is therefore critical. In this study, we observed that the kinase, GSK-3ß, is present in its active form in resting immature DCs isolated from the spleen and bone marrow of mice. Induction of DC maturation using GM-CSF, IL-4 and TNF-α resulted in GSK-3ß inhibition, as reflected by increased phosphorylation of Serine 9 on the kinase, and concomitant stabilization of its substrate, ß-catenin. Treatment of immature DCs with a GSK-3ß inhibitor increased cell surface expression of CD80, CD86 and CD40 on DCs, enhancing their ability to present antigen and activating IL-2 secretion by T cells. GSK-3ß inhibition also parallels dendritic cell maturation in vivo. Our results show that GSK-3ß signaling controls DC maturation and suggest that this kinase could be manipulated to modulate adaptive immunity.

Facilitators and barriers of care transitions - Comparing the perspectives of hospital and community healthcare staff.

As a patient moves from hospital back home to receive community-based care, quality of care and patient safety are often put at risk. This study aimed to analyse the discharge process to identify and compare the barriers and facilitators within the context of the system in which they occur, from the perspectives of both hospital and community healthcare staff. The results were derived from the analysis of 348 incident reports, the observation of five discharge planning meetings with hospital staff, three focus groups with hospital staff, and six focus groups with community healthcare staff. Five themes representative of the barriers and four themes representative of the facilitators for this process were identified from both hospital and community healthcare staff's perspective. These were then discussed in the context of the subsystem, hospital or community healthcare setting, in which they occur.

Immune recognition and rejection of allogeneic skin grafts.

The transplantation of allogeneic skin grafts is associated with a potent inflammatory immune response leading to the destruction of donor cells and the rejection of the graft. Shortly after transplantation, skin dendritic cells (DCs) migrate out of the graft through lymphatic vessels and infiltrate the recipient's draining lymph nodes where they present donor antigens via two mechanisms: the direct pathway, in which T cells recognize intact donor MHC antigens on donor DCs; and the indirect pathway, involving T-cell recognition of donor peptides bound to self-MHC molecules on recipient DCs. Some recent studies have suggested that T cells can become activated via recognition of donor MHC molecules transferred on recipient antigen-presenting cells (semidirect pathway). Activation of T cells via direct or indirect allorecognition is sufficient to trigger acute rejection of allogeneic skin grafts. In addition, allospecific antibodies contribute to the rejection process either by killing allogeneic targets in a complement-dependent fashion or by opsonizing donor cells and forming immune complexes. Finally, several studies demonstrate that NK cells, activated due to missing self-MHC class I molecules on allogeneic cells, are involved in allogeneic skin graft rejection via direct killing of donor cells and through the production of proinflammatory cytokines including IFN-γ and TNF-α.