TIM3 is a context-dependent coregulator of cytotoxic T cell function

Cytotoxic T lymphocytes (CTLs) are essential effectors in the antiviral and antitumour immune response and attractive targets in cancer immunotherapy. Although CTLs can directly recognise and kill tumour cells, CTLs become suppressed in the tumour microenvironment. This project investigated the inhibitory receptor T cell immunoglobulin and mucin domain 3 (TIM3). TIM3 is expressed on T cells after chronic antigen exposure and marks the most exhausted tumour infiltrating CTLs in multiple solid tumours. However, it is unclear whether TIM3 directly regulates CTL function. In addition, despite its predominantly inhibitory role in vivo, TIM3 can promote cellular activation in T and non-T cells, and the roles of putative ligands in TIM3 function are disputed. Therefore, we aimed to determine the effect of TIM3 on direct CTL antitumour function and how the TIM3 ligands Galectin9 (GAL9) and CEACAM1 regulate its function. We employed three-dimensional (3D) tumour spheroids that effectively induce CTL suppression similar to the in vivo tumour microenvironment in comparison to conventional two-dimensional (2D) tumour cell culture. In the 3D spheroid model, TIM3 significantly inhibited CTL cytotoxicity and cytoskeletal polarisation as a key mechanism of effective cytolysis in murine and human CTLs. In contrast, in the 2D tumour model, TIM3 stimulated CTL cytotoxicity, cytoskeletal polarisation, and secretion of the immune-stimulatory cytokine interferon γ (IFNγ). Expression of GAL9 and CEACAM1 in trans on tumour cells further suppressed the CTL killing ability in the 3D spheroid model and enhanced costimulatory function in 2D. CEACAM1 in cis neutralised TIM3 functions in both 3D and 2D. We suggest that TIM3 functions as a context-dependent coregulatory receptor, as supported by the engagement of its ligands GAL9 and CEACAM1. In a largely stimulatory signalling context of a CTL, TIM3 functions as a costimulator, and in a more inhibitory context, TIM3 functions as a coinhibitor

Anti-corruption disclosure and corporate governance mechanisms: insights from FTSE 100

Purpose: This study examines the impact of corporate governance (CG) on anti-corruption disclosure (A-CD), paying particular attention to FTSE 100. Notably, it examines how board and audit committees’ characteristics affect the quantity and quality of anti-corruption disclosure. Design/Methodology: Data from FTSE 100 firms, spanning the period from 2014 to 2020 were analysed using the regression of Poisson fixed effect and GEE analyses. Findings: The findings show that gender diversity, audit committee expertise and the independence of the audit committee are positively associated with both quantity and quality of anti-corruption disclosure. Notably, no statistically significant relationships were identified between anti-corruption disclosure and factors such as board size, role duality, or board meetings. Implications: Our findings provide valuable insights for decision-makers and regulatory bodies, shedding light on the elements that compel UK companies to enhance their anti-corruption disclosure and governance protocols to alleviate corruption and propel efforts towards ethical behaviour. Originality: This study makes a notable contribution to the sparse body of evidence by examining the influence of board and audit committee attributes on anti-corruption disclosure subsequent to the implementation of the UK Bribery Act in 2010. Specifically, to the best of the authors' knowledge, this study assesses for the first time the impact of board and audit committee mechanisms on both the quantity and quality of anti-corruption disclosure

Effects of Disorder and Interactions in the Quantum Hall Ferromagnet

This work treats the effects of disorder and interactions in a quantum Hall ferromagnet, which is realized in a two-dimensional electron gas (2DEG) in a perpendicular magnetic field at Landau level filling factor equal one. We study the problem by projecting the original fermionic Hamiltonian into magnon states, which behave as bosons in the vicinity of the ferromagnetic ground state. The approach permits the reformulation of a strongly interacting model into a non-interacting one. The latter is a non-perturbative scheme that consists in treating the two-particle neutral excitations of the electron system as a bosonic single-particle. Indeed, the employment of bosonization facilitates the inclusion of disorder in the study of the system. It has been shown previously that disorder may drive a quantum phase transition in the Hall ferromagnet. However, such studies have been either carried out in the framework of nonlinear sigma model, as an effective low-energy theory, or included the long-range Coulomb interaction in a quantum description only up to the Hartree-Fock level. Here, we establish the occurrence of a disorder-driven quantum phase transition from a ferromagnetic 2DEG to a spin glass phase by taking into account interactions between electrons up to the random phase approximation level in a fully quantum description.Comment: 18 pages, 7 figure

Cellular Structures Controlling T Cell Signaling in Time and Space

T cell signaling is characterized by the diverse enrichment of receptors and signaling intermediates at particular subcellular regions of the T cell at specific times, resulting in complex spatiotemporal signaling distributions. These signaling distributions control the flow of information through the T cell signaling network and thus govern the efficiency of cellular activation. Here we discuss principal cellular structures driving the organization of T cell signaling including membrane topology, vesicular trafficking, cytoskeletal structures and protein complexes

Pseudotumor cerebri in a child receiving peritoneal dialysis: recovery of vision after lumbo-pleural shunt

A 9-year-old boy with end-stage renal disease who was receiving continuous ambulatory peritoneal dialysis (CAPD) presented with acute visual loss and was found to have papilledema. Neuroimaging and cerebrospinal fluid (CSF) analysis were normal. The lumbar puncture opening pressure was 290 mm of water so the diagnosis of pseudotumor cerebri (PTC) was entertained. Medical treatment was not an option because of renal insufficiency; neither was lumbo-peritoneal shunting, because of the peritoneal dialysis. After a lumbo-pleural shunt was placed, there was marked improvement in symptoms. The lumbo-pleural shunt is a reasonable option for treatment for PTC in patients on CAPD who require a CSF divergence procedure