Hepatic NK cells eliminate HBV-specific T cells dependent on TRAIL and TRAIL-R2 interactions to limit antiviral immunity in chronic infection.

The S-type lectin galectin-9 binds to the negative regulatory molecule Tim-3 on T cells and induces their apoptotic deletion or functional inactivation. We investigated whether galectin-9/Tim-3 interactions contribute to the deletion and exhaustion of the antiviral T cell response in chronic hepatitis B virus infection (CHB). We found Tim-3 to be expressed on a higher percentage of CD4 and CD8 T cells from patients with CHB than healthy controls (p<0.0001) and to be enriched on activated T cells and those infiltrating the HBV-infected liver. Direct ex vivo examination of virus-specific CD8 T cells binding HLA-A2/peptide multimers revealed that Tim-3 was more highly upregulated on HBV-specific CD8 T cells than CMV-specific CD8 T cells or the global CD8 T cell population in patients with CHB (p<0.001) or than on HBV-specific CD8 after resolution of infection. T cells expressing Tim-3 had an impaired ability to produce IFN-γ and TNF-α upon recognition of HBV-peptides and were susceptible to galectin-9-triggered cell death in vitro. Galectin-9 was detectable at increased concentrations in the sera of patients with active CHB-related liver inflammation (p = 0.02) and was strongly expressed by Kupffer cells within the liver sinusoidal network. Tim-3 blockade resulted in enhanced expansion of HBV-specific CD8 T cells able to produce cytokines and mediate cytotoxicity in vitro. Blocking PD-1 in combination with Tim-3 enhanced the number of patients from whom functional antiviral responses could be recovered and/or the strength of responses, indicating that these co-inhibitory molecules play a non-redundant role in driving T cell exhaustion in CHB. Patients taking antivirals able to potently suppress HBV viraemia continued to express Tim-3 on their T cells and respond to Tim-3 blockade. In summary, both Tim-3 and galectin-9 are increased in CHB and may contribute to the inhibition and deletion of T cells as they infiltrate the HBV-infected liver.

OBJECTIVETo perform the first comprehensive psychometric evaluation of the Hypoglycemia Fear Survey-II (HFS-II), a measure of the behavioral and affective dimensions of fear of hypoglycemia, using modern test-theory methods, including item-response theory (IRT).RESEARCH DESIGN AND METHODSSurveys completed in four previous studies by 777 adults with type 1 diabetes were aggregated for analysis, with 289 subjects completing both subscales of the HFS-II and 488 subjects completing only the Worry subscale. The aggregated sample (53.3% female, 44.4% using insulin pumps) had a mean age of 41.9 years, diabetes duration of 23.8 years, HbA1c value of 7.7%, and 1.4 severe hypoglycemic episodes in the past year. Data analysis included exploratory factor analysis using polychoric correlations and IRT. Factors were analyzed for fit, trait-level locations, point-measure correlations, and separation values.RESULTSInternal and test-retest reliability was good, as well as convergent validity, as demonstrated by significant correlations with other measures of psychological distress. Scores were significantly higher in subjects who had experienced severe hypoglycemia in the past year. Factor analyses validated the two subscales of the HFS-II. Item analyses showed that 12 of 15 items on the Behavior subscale, and all of the items on the Worry subscale had good-fit statistics.CONCLUSIONSThe HFS-II is a reliable and valid measure of the fear of hypoglycemia in adults with type 1 diabetes, and factor analyses and IRT support the two separate subscales of the survey.

Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12.IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections.

As a common side effect of insulin treatment for diabetes, hypoglycaemia is a constant threat and can have far-reaching and potentially devastating consequences, including immediate physical injury as well as more pervasive cognitive, behavioural and emotional effects. Moreover, as a significant limiting factor in achieving optimal glycaemic control, exposure to hypoglycaemia can influence diabetes self-management. Although hypoglycaemia is known to occur in Type 2 diabetes, its morbidity and impact on the individual are not well recognized. The aim of the current review is to examine published evidence to achieve a synthesis of the scope and significance of the potential detriment caused by hypoglycaemia to individuals with Type 2 diabetes. The implications of these observations for treatment and research have also been considered. A narrative review was performed of empirical papers published in English since 1966, reporting the effect of hypoglycaemia on quality of life and related outcomes (including generic and diabetes-specific quality of life, emotional well-being and health utilities) in Type 2 diabetes. Research demonstrates the potential impact of hypoglycaemia on the lives of people with Type 2 diabetes, from an association with depressive symptoms and heightened anxiety, to impairment of the ability to drive, work and function in ways that are important for quality of life. Few studies consider hypoglycaemia as an explanatory variable in combination with quality of life or related primary endpoints. As a consequence, there is a pressing need for high-quality research into the overall impact of hypoglycaemia on the lives of people with Type 2 diabetes.