The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated.Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually.We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails

PROGRESS TOWARDS HIGH PERFORMANCE PLASMAS IN THE NATIONAL SPHERICAL TORUS EXPERIMENT (NSTX)

The major objective of the National Spherical Torus Experiment (NSTX) is to understand basic toroidal confinement physics at low aspect ratio and high beta(T) in order to advance the spherical torus (ST) concept. In order to do this, NSTX utilizes up to 7.5 MW of neutral beam injection, up to 6 MW of high harmonic fast waves (HHFWs), and it operates with plasma currents up to 1.5 MA and elongations of up to 2.6 at a toroidal field up to 0.45 T. New facility, and diagnostic and modelling capabilities developed over the past two years have enabled the NSTX research team to make significant progress towards establishing this physics basis for future ST devices. Improvements in plasma control have led to more routine operation at high elongation and high beta(T) (up to similar to 40%) lasting for many energy confinement times. beta(T) can be limited by either internal or external modes. The installation of an active error field (EF) correction coil pair has expanded the operating regime at low density and has allowed for initial resonant EF amplification experiments. The determination of the confinement and transport properties of NSTX plasmas has benefitted greatly from the implementation of higher spatial resolution kinetic diagnostics. The parametric variation of confinement is similar to that at conventional aspect ratio but with values enhanced relative to those determined from conventional aspect ratio scalings and with a B-T dependence. The transport is highly dependent on details of both the flow and magnetic shear. Core turbulence was measured for the first time in an ST through correlation reflectometry. Non-inductive start-up has been explored using PF-only and transient co-axial helicity injection techniques, resulting in up to 140 kA of toroidal current generated by the latter technique. Calculated bootstrap and beam-driven currents have sustained up to 60% of the flat-top plasma current in NBI discharges. Studies of HHFW absorption have indicated parametric decay of the wave and associated edge thermal ion heating. Energetic particle modes, most notably toroidal Alfven eigenmodes and fishbone-like modes result in fast particle losses, and these instabilities may affect fast ion confinement on devices such as ITER. Finally, a variety of techniques has been developed for fuelling and power and particle control.X1145sciescopu

Overview of recent physics results from the national spherical torus experiment (NSTX)

The National Spherical Torus Experiment (NSTX) has made considerable progress in advancing the scientific understanding of high performance long-pulse plasmas needed for future spherical torus (ST) devices and ITER. Plasma durations up to 1.6 s (five current redistribution times) have been achieved at plasma currents of 0.7 MA with non-inductive current fractions above 65% while simultaneously achieving beta(T) and beta(N) values of 17% and 5.7 (%m T MA(-1)), respectively. A newly available motional Stark effect diagnostic has enabled validation of current-drive sources and improved the understanding of NSTX 'hybrid'-like scenarios. In MHD research, ex-vessel radial field coils have been utilized to infer and correct intrinsic EFs, provide rotation control and actively stabilize the n = 1 resistive wall mode at ITER-relevant low plasma rotation values. In transport and turbulence research, the low aspect ratio and a wide range of achievable in the NSTX provide unique data for confinement scaling studies, and a new microwave scattering diagnostic is being used to investigate turbulent density fluctuations with wavenumbers extending from ion to electron gyro-scales. In energetic particle research, cyclic neutron rate drops have been associated with the destabilization of multiple large toroidal Alfven eigenmodes (TAEs) analogous to the 'sea-of-TAE' modes predicted for ITER, and three-wave coupling processes have been observed for the first time. In boundary physics research, advanced shape control has enabled studies of the role of magnetic balance in H-mode access and edge localized mode stability. Peak divertor heat flux has been reduced by a factor of 5 using an H-mode-compatible radiative divertor, and lithium conditioning has demonstrated particle pumping and results in improved thermal confinement. Finally, non-solenoidal plasma start-up experiments have achieved plasma currents of 160 kA on closed magnetic flux surfaces utilizing coaxial helicity injection.X1132Nsciescopu