The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement. Phosphorylated LAT binds many critical signaling molecules. The central role of this molecule in TCR-mediated signaling has been demonstrated by experiments in a LAT-deficient cell line. To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting. LAT-deficient mice appeared healthy. Flow cytometric analysis revealed normal B cell populations but the absence of any mature peripheral T cells. Intrathymic development was blocked within the CD4- CD8- stage. No gross abnormality of NK or platelet function was observed. LAT is thus critical to both T cell activation and development.

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Here, we present data suggesting a novel mechanism for regulation of natural killer (NK) cell cytotoxicity through inhibitory receptors. Interaction of activation receptors with their ligands on target cells induces cytotoxicity by NK cells. This activation is under negative control by inhibitory receptors that recruit tyrosine phosphatase SHP-1 upon binding major histocompatibility class I on target cells. How SHP-1 blocks the activation pathway is not known. To identify SHP-1 substrates, an HLA-C-specific inhibitory receptor fused to a substrate-trapping mutant of SHP-1 was expressed in NK cells. Phosphorylated Vav1, a regulator of actin cytoskeleton, was the only protein detectably associated with the catalytic site of SHP-1 during NK cell contact with target cells expressing HLA-C. Vav1 trapping was independent of actin polymerization, suggesting that inhibition of cellular cytotoxicity occurs through an early dephosphorylation of Vav1 by SHP-1, which blocks actin-dependent activation signals. Such a mechanism explains how inhibitory receptors can block activating signals induced by different receptors.In many cell types, activation induced by cell contact is controlled by inhibitory receptors that bind ligands on target cells (41, 48). The importance of this type of negative regulation is illustrated by the protection of normal cells from lysis by NK cells, of red blood cells from ingestion by macrophages (44), and of cardiomyocytes from immunoglobulin G (IgG)-mediated autoimmunity (43). A common feature of the receptors involved in these protective functions (i.e., CD158, SIRP-␣, and PD-1, respectively) and of many other receptors that inhibit cellular responses is the presence of immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic tail (12,48). Upon Tyr phosphorylation, ITIMs bind to the SH2 domains of protein tyrosine phosphatases (PTPases) SHP-1 and SHP-2, thereby releasing the catalytic site from autoinhibition (2, 12). Activation of human NK cell and T cell cytotoxicity is controlled by several inhibitory receptors, including the CD158 killer cell Ig-like receptors (KIR) and the lectin-like CD94/NKG2A, which bind to major histocompatibility complex (MHC) class I molecules expressed on target cells (5).Whereas the functional consequence of SHP-1 recruitment by ITIM-containing receptors in NK cells is well established, the specific point at which SHP-1 blocks activation signals has not been defined. Engagement of inhibitory receptors by ligands on target cells blocks conjugate formation (13), Ca 2ϩ flux (38, 52), polarization of lipid rafts in NK cells (42), and actin cytoskeleton rearrangement in T cells (26). As NK cell cytotoxicity depends on the activity of Tyr kinases (40), a number of Tyr-phosphorylated proteins are potential substrates for dephosphorylation by SHP-1. Two nonexclusive models, a "promiscuous" and a "selective" model, can be proposed for SHP-1-mediated inhibition. First, recruitment and activation of SHP-1 by inhibitory receptors at the NK-target cell interfac...