A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gainof-function inhibition of T cell signaling.

OBJECTIVEThe Pediatric Artificial Pancreas (PedArPan) project tested a children-specific version of the modular model predictive control (MMPC) algorithm in 5-to 9-yearold children during a camp. RESEARCH DESIGN AND METHODSA total of 30 children, 5-to 9-years old, with type 1 diabetes completed an outpatient, open-label, randomized, crossover trial. Three days with an artificial pancreas (AP) were compared with three days of parent-managed sensoraugmented pump (SAP). RESULTSOvernight time-in-hypoglycemia was reduced with the AP versus SAP, median (25 th -75 th percentiles): 0.0% (0.0-2.2) vs. 2.2% (0.0-12.3) (P 5 0.002), without a significant change of time-in-target, mean: 56.0% (SD 22.5) vs. 59.7% (21.2) (P 5 0.430), but with increased mean glucose 173 mg/dL (36) vs. 150 mg/dL (39) (P 5 0.002). Overall, the AP granted a threefold reduction of time-in-hypoglycemia (P < 0.001) at the cost of decreased time-in-target, 56.8% (13.5) vs. 63.1% (11.0) (P 5 0.022) and increased mean glucose 169 mg/dL (23) vs. 147 mg/dL (23) (P < 0.001). CONCLUSIONSThis trial, the first outpatient single-hormone AP trial in a population of this age, shows feasibility and safety of MMPC in young children. Algorithm retuning will be performed to improve efficacy.Only three artificial pancreas (AP) trials have focused on the prepubertal population so far: two single-hormone AP studies, performed inpatient for less than 1 day (1,2) and a recent dual-hormone AP study, performed in a camp for 5 days (3). Here we report the first outpatient single-hormone AP trial focusing on 5-to 9-year-old children.Data were collected in the Pediatric Artificial Pancreas (PedArPan) camp, where sensor-augmented pump (SAP) therapy was compared with the modular model predictive control algorithm (MMPC) (4,5), running on the wearable platform Diabetes Assistant (DiAs) (6).

Activation of T cells is largely mediated through signal transduction downstream from the T-cell receptor (TCR) expressed on the cell surface. The TCR is a transmembrane receptor complex comprised of a and b chains, which bind ligands, and CD3 (e, c and d) and f chains containing motifs that are phosphorylated on tyrosine, called immunoreceptor tyrosine-based activation motifs. Signal transduction through the TCR is initiated when the receptor binds to a peptide-MHC complex presented by an antigen-presenting cell. This interaction initiates a cascade of signalling events, which induces the proliferation, mobilization and differentiation of T cells. For an updated and comprehensive review of signalling through the TCR the reader is referred to recent authoritative publications. [1][2][3][4] A dynamic wave of tyrosine phosphorylation phenomena is critical for ignition of intracellular signalling in T cells. Engagement of the TCR leads to the activation of the Src family protein tyrosine kinases (PTKs) LCK and FYN, which phosphorylate the immunoreceptor tyrosinebased activation motifs of the TCR. This provides docking sites for the SH2 domains of ZAP-70, a Syk family PTK, allowing ZAP-70 to be phosphorylated and activated by LCK. Once activated, ZAP-70 phosphorylates the adaptor proteins SLP-76 and LAT, which nucleate signalling complexes, leading to the phosphorylation and activation of multiple downstream effectors. This results in calcium mobilization, activation of mitogen-activated protein kinases (MAPKs), transcriptional regulation and cytoskeletal rearrangements.Protein tyrosine phosphatases (PTPs) are the natural counterpart of PTKs. Much like PTKs, depending upon the phosphorylation site and the signalling context, they can enhance or reduce the function of their protein target(s). The modern view of phosphorylation networks is one of dynamic 'always-on' grids where the stoichiometry of each phosphorylation site is continuously controlled by the changing balance between the activities of kinases and phosphatases. For example, the activation state of the Src family kinases (SFKs) is balanced between the activities of CSK and CD45, which respectively phosphorylate and dephosphorylate the inhibitory C-terminal site (Y505 of LCK), and the negative regulators LYP and SHP-1, which dephosphorylate an activating tyrosine in the catalytic domain (Y394 of LCK). Acute changes in PTP activity/ expression are in principle sufficient to alter the network status and even trigger true signalling waves. The recent 'kinetic-segregation' model postulates that PTPs are responsible for the very initiation of signalling after engagement of the TCR. SummaryMore than half of the known protein tyrosine phosphatases (PTPs) in the human genome are expressed in T cells, and significant progress has been made in elucidating the biology of these enzymes in T-cell development and function. Here we provide a systematic review of the current understanding of the roles of PTPs in T-cell activation, providing insight into their mechanisms ...

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