Stomatin-like Protein 2 Links Mitochondria to T-Cell Receptor Signalosomes at the Immunological Synapse and Enhances T-Cell Activation

T cell activation through the antigen receptor (TCR) requires sustained signalling from microclusters in the peripheral region of the immunological synapse (IS). The bioenergetics of such prolonged signaling have been linked to the redistribution of mitochondria to the IS. Here, we report that stomatin-like protein-2 (SLP-2) plays an important role in this process by bridging polarized mitochondria to these signaling TCR microclusters or signalosomes in the IS in a polymerized actin-dependent manner. In this way, SLP-2 helps to sustain TCR-dependent signalling and enhances T cell activation

Determinants of Influenza Mortality Trends: Age-Period-Cohort Analysis of Influenza Mortality in the United States, 1959-2016.

This study examines the roles of age, period, and cohort in influenza mortality trends over the years 1959-2016 in the United States. First, we use Lexis surfaces based on Serfling models to highlight influenza mortality patterns as well as to identify lingering effects of early-life exposure to specific influenza virus subtypes (e.g., H1N1, H3N2). Second, we use age-period-cohort (APC) methods to explore APC linear trends and identify changes in the slope of these trends (contrasts). Our analyses reveal a series of breakpoints where the magnitude and direction of birth cohort trends significantly change, mostly corresponding to years in which important antigenic drifts or shifts took place (i.e., 1947, 1957, 1968, and 1978). Whereas child, youth, and adult influenza mortality appear to be influenced by a combination of cohort- and period-specific factors, reflecting the interaction between the antigenic experience of the population and the evolution of the influenza virus itself, mortality patterns of the elderly appear to be molded by broader cohort factors. The latter would reflect the processes of physiological capital improvement in successive birth cohorts through secular changes in early-life conditions. Antigenic imprinting, cohort morbidity phenotype, and other mechanisms that can generate the observed cohort effects, including the baby boom, are discussed

Pandemic Paradox: Early Life H2N2 Pandemic Influenza Infection Enhanced Susceptibility to Death during the 2009 H1N1 Pandemic.

Recent outbreaks of H5, H7, and H9 influenza A viruses in humans have served as a vivid reminder of the potentially devastating effects that a novel pandemic could exert on the modern world. Those who have survived infections with influenza viruses in the past have been protected from subsequent antigenically similar pandemics through adaptive immunity. For example, during the 2009 H1N1 "swine flu" pandemic, those exposed to H1N1 viruses that circulated between 1918 and the 1940s were at a decreased risk for mortality as a result of their previous immunity. It is also generally thought that past exposures to antigenically dissimilar strains of influenza virus may also be beneficial due to cross-reactive cellular immunity. However, cohorts born during prior heterosubtypic pandemics have previously experienced elevated risk of death relative to surrounding cohorts of the same population. Indeed, individuals born during the 1890 H3Nx pandemic experienced the highest levels of excess mortality during the 1918 "Spanish flu." Applying Serfling models to monthly mortality and influenza circulation data between October 1997 and July 2014 in the United States and Mexico, we show corresponding peaks in excess mortality during the 2009 H1N1 "swine flu" pandemic and during the resurgent 2013-2014 H1N1 outbreak for those born at the time of the 1957 H2N2 "Asian flu" pandemic. We suggest that the phenomenon observed in 1918 is not unique and points to exposure to pandemic influenza early in life as a risk factor for mortality during subsequent heterosubtypic pandemics.IMPORTANCE The relatively low mortality experienced by older individuals during the 2009 H1N1 influenza virus pandemic has been well documented. However, reported situations in which previous influenza virus exposures have enhanced susceptibility are rare and poorly understood. One such instance occurred in 1918-when those born during the heterosubtypic 1890 H3Nx influenza virus pandemic experienced the highest levels of excess mortality. Here, we demonstrate that this phenomenon was not unique to the 1918 H1N1 pandemic but that it also occurred during the contemporary 2009 H1N1 pandemic and 2013-2014 H1N1-dominated season for those born during the heterosubtypic 1957 H2N2 "Asian flu" pandemic. These data highlight the heretofore underappreciated phenomenon that, in certain instances, prior exposure to pandemic influenza virus strains can enhance susceptibility during subsequent pandemics. These results have important implications for pandemic risk assessment and should inform laboratory studies aimed at uncovering the mechanism responsible for this effect

The Immunological Synapse as a Novel Therapeutic Target

The onset of adaptive immune responses includes the presentation of foreign antigenic peptides to T-cells, and the formation of a T-cell-antigen-presenting cell interface termed the immunological synapse (IS). Although the generation of a mature IS is thought to be the hallmark of T-cell activation, new evidence suggests that microclusters ofat signaling molecules at the periphery of the IS are responsible for initiating and maintaining T-cell activation while the core of the IS provides a platform for signal downregulation. In this context, costimulatory molecules and self-peptides contribute to sustain the signaling required for T-lymphocyte differentiation into effector cells. This review discusses these aspects in the identification of novel candidates for therapeutic modulation of immune responses

Surgical Technique for Vascularized Thymus Transplantation in Mice

Traditionally, mouse nonvascularized thymus implants have been used to investigate various aspects of thymus function. However, these grafts are easily damaged by ischemia and fail to reproduce the normal anatomy of the thymus. In addition, the function of these grafts has not been fully examined. We have recently developed a vascularized thymus transplant model in mice. The donor operation consists of isolating the right lobe of the thymus and creating a single vascular pathway. In the recipient surgery, end-to-side anastomoses between donor brachycephalic artery and recipient right common carotid artery, and between donor superior caval vein and recipient right external jugular vein, were performed. We performed 10 consecutive isografts in BALB/c mice with a success rate of 90%. The thymus grafts had a normal histology and function. This study illustrates that it is technically possible to transplant a mouse vascular thymus graft. This model has several advantages that make it a useful tool to study many aspects of thymus function. We plan to use this model further to study the potential for induction of tolerance by thymus grafts

The Future of RIP2/RICK/CARDIAK as a Biomarker of the Inflammatory Response to Infection

Biological markers of disease have become increasingly important for the clinician to diagnose, predict and monitor progression, and assess the therapeutic effect of interventions on underlying pathogenic mechanisms. Robust and specific biomarkers would be very useful in inflammation, where they may facilitate early identification of tissue injury, predict disease progression and help to modify disease outcomes. However, at present, there are no robust biomarkers to predict the course of inflammation. Here, we discuss emerging data indicating that RIP2, a putative serine/threonine protein kinase, may serve as a biomarker for the resolution of peritoneal dialysis-associated peritonitis and, more generally, of the acute inflammatory response to infection