Outflanking RANK with a designer antagonist cytokine.

Members of the tumor necrosis factor (TNF) superfamily of cytokines are noncovalently linked trimers that play important roles in regulating the immune system and have emerged as successful therapeutic targets in various rheumatic and autoimmune conditions. Traditionally, antibodies to cytokines or receptor-Fc fusion proteins have been used to block signaling by TNF family cytokines. In this issue of Science Signaling, Warren et al.

The role of LAT-PLCγ1 interaction in γδ T cell development and homeostasis.

LAT is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals to modulate T cell development, activation, and proliferation. Upon T cell activation, LAT is phosphorylated and associates with Grb2, Gads, and PLCγ1 through its four distal tyrosine residues. Mutation of one of these tyrosines, Y136, abolishes LAT binding to PLCγ1.

The requirement of linker for activation of T cells in the primary and memory responses of CD8 T cells.

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that links TCR engagement to downstream signaling events. Although it is clear that LAT is essential in thymocyte development and initiation of T cell activation, its function during T cell expansion, contraction, and memory formation remains unknown. To study the role of TCR-mediated signaling in CD8 T cells during the course of pathogen infection, we used an inducible mouse model to delete LAT in Ag-specific CD8 T cells at different stages of Listeria infection and analyzed the effect of deletion on T cell responses.

Computational and bioinformatics frameworks for next-generation whole exome and genome sequencing.

It has become increasingly apparent that one of the major hurdles in the genomic age will be the bioinformatics challenges of next-generation sequencing. We provide an overview of a general framework of bioinformatics analysis. For each of the three stages of (1) alignment, (2) variant calling, and (3) filtering and annotation, we describe the analysis required and survey the different software packages that are used.

Personalizing rare disease research: how genomics is revolutionizing the diagnosis and treatment of rare disease.

A decade after the complete sequencing of the human genome, combined with recent advances in throughput and sequencing costs, the genetics of rare diseases has entered a new era. There has now been an explosion in the identification and mapping of rare diseases, with over 10,000 exomes having been sequenced to date. This article surveys the progress and development of technologies to understand rare disease; it provides a historical overview of traditional techniques such as karyotyping and homozygosity mapping, reviews current methods of whole-exome and -genome sequencing, and provides a future perspective on upcoming developments such as targeted drugs and gene therapy.

Regulation of RasGRP1 function in T cell development and activation by its unique tail domain.

The Ras-guanyl nucleotide exchange factor RasGRP1 plays a critical role in T cell receptor-mediated Erk activation. Previous studies have emphasized the importance of RasGRP1 in the positive selection of thymocytes, activation of T cells, and control of autoimmunity. RasGRP1 consists of a number of well-characterized domains, which it shares with its other family members; however, RasGRP1 also contains an ~200 residue-long tail domain, the function of which is unknown.

Role of LAT in the granule-mediated cytotoxicity of CD8 T cells.

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is essential to bridge T cell receptor (TCR) engagement to downstream signaling events. The indispensable role of LAT in thymocyte development and T cell activation has been well characterized; however, the function of LAT in cytotoxic-T-lymphocyte (CTL) cytotoxicity remains unknown. We show here that LAT-deficient CTLs failed to upregulate FasL and produce gamma interferon after engagement with target cells and had impaired granule-mediated killing.

Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB.

Linker for activation of B cells (LAB)/non-T cell activation linker is a transmembrane adaptor protein that functions in immunoreceptor-mediated signaling. Published studies have shown that LAB has both positive and negative roles in regulating TCR and high-affinity Fc receptor-mediated signaling and cellular function. In this study, we showed that LAB was also expressed in dendritic cells and that LAB deficiency affected LPS-mediated signaling and cytokine production.

Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCRα gene expression.

In contrast to the well-characterized T cell receptor (TCR) signaling pathways that induce genes that drive T cell development or polarization of naïve CD4 T cells into the diverse T(H)1, T(H)2, T(H)17 and T(reg) lineages, it is unclear what signals maintain specific gene expression in mature resting T cells. Resting T cells residing in peripheral lymphoid organs exhibit low-level constitutive signaling. Whereas tonic signals in B cells are known to be critical for survival, the roles of tonic signals in peripheral T cells are unknown.

A tale of two TRAPs: LAT and LAB in the regulation of lymphocyte development, activation, and autoimmunity.

Transmembrane adaptor proteins (TRAPs) link antigen receptor engagement to downstream cellular processes. Although these proteins typically lack intrinsic enzymatic activity, they are phosphorylated on multiple tyrosine residues following lymphocyte activation, allowing them to function as scaffolds for the assembly of multi-molecular signaling complexes. Among the many TRAPs that have been discovered in recent years, the LAT (linker for activation of T cells) family of adaptor proteins plays an important role in the positive and negative regulation of lymphocyte maturation, activation, and differentiation.

The importance of LAT in the activation, homeostasis, and regulatory function of T cells.

LAT (linker for activation of T cells) is a transmembrane adaptor protein that plays an essential role in TCR-mediated signaling and thymocyte development. Because LAT-deficient mice have an early block in thymocyte development, we utilized an inducible system to delete LAT in primary T cells to study LAT function in T cell activation, homeostasis, and survival. Deletion of LAT caused primary T cells to become unresponsive to stimulation from the TCR and impaired T cell homeostatic proliferation and long term survival.

HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can involve MHC-restricted presentation of a drug or its metabolites for T-cell activation. HLA-B(*)1502 tightly associated with carbamazepine (CBZ) induced these conditions in a Han Chinese population.

Objective: We sought to identify HLA-B(*)1502-bound peptides that might be involved in CBZ-induced SJS/TEN.