Immediate Cytotoxicity But Not Degranulation Distinguishes Effector and Memory Subsets of CD8+ T Cells

CD8+ T cells play a central role in the resolution and containment of viral infections. A key effector function of CD8+ T cells is their cytolytic activity toward infected cells. Here, we studied the regulation of cytolytic activity in naive, effector, and central versus effector memory CD8+ T cells specific for the same glycoprotein-derived epitope of lymphocytic choriomeningitis virus. Our results show that the kinetics of degranulation, assessed by a novel flow cytometric based assay, were identical in effector and both subsets of memory CD8+ T cells, but absent in naive CD8+ T cells. However, immediate cytolytic activity was most pronounced in effector T cells, low in effector memory T cells, and absent in central memory T cells, correlating with the respective levels of cytolytic effector molecules present in lytic granules. These results indicate that an inherent program of degranulation is a feature of antigen-experienced cells as opposed to naive CD8+ T cells and that the ability of CD8+ T cells to induce target cell apoptosis/death is dependent on granule protein content rather than on the act of degranulation itself. Furthermore, these results provide a potential mechanism by which central memory CD8+ T cell–mediated death of antigen-presenting cells within the lymph node is avoided

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

Immunological memory is a hallmark of adaptive immunity, and understanding T cell memory will be central to the development of effective cell-mediated vaccines. The characteristics and functions of CD4 memory cells have not been well defined. Here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. Memory cells proliferated less than primary responding cells, even within the same host. By analyzing the entry of primary and memory cells into the cell cycle, we found that the two populations proliferated similarly until day 5; after this time, fewer of the reactivated memory cells proliferated. At this time, fewer of the reactivated memory cells made IL-2 than primary responding cells, but more made IFNγ. Both these factors affected the low proliferation of the memory cells, because either exogenous IL-2 or inhibition of IFNγ increased the proliferation of the memory cells

Dynamics of Relativistic Interacting Gases : from a Kinetic to a Fluid Description

Starting from a microscopic approach, we develop a covariant formalism to describe a set of interacting gases. For that purpose, we model the collision term entering the Boltzmann equation for a class of interactions and then integrate this equation to obtain an effective macroscopic description. This formalism will be useful to study the cosmic microwave background non-perturbatively in inhomogeneous cosmologies. It should also be useful for the study of the dynamics of the early universe and can be applied, if one considers fluids of galaxies, to the study of structure formation.Comment: Latex file, 28 pages, accepted for publication in Class. Quant. Gra

HIV-Specific Cellular Immune Response Is Inversely Correlated with Disease Progression as Defined by Decline of CD4+ T Cells in Relation to HIV RNA Load

The average time between infection with human immunodeficiency virus (HIV) and development of acquired immune deficiency syndrome is ∼8 years. However, progression rates vary widely, depending on several determinants, including HIV-specific immunity, host genetic factors, and virulence of the infecting strain. In untreated HIV-infected patients with different progression rates, we examined HIV-specific T cell responses in combination with host genetic markers, such as chemokine/chemokine-receptor (CCR) polymorphisms and human leukocyte antigen (HLA) genotypes. HIV-specific CD4+ T cell responses and, to a lesser extent, HIVspecific CD8+ T cell responses were inversely correlated with progression rate. Slower progression was not related to polymorphisms in CCR genes, HLA genotype, or GB virus C coinfection. These data suggest that HIV-specific T cell responses are involved in protecting the host from disease progressio

Swiss Adult Congenital HEart disease Registry (SACHER) - rationale, design and first results.

In 2013, a prospective registry for adults with congenital heart disease (CHD) was established in Switzerland, providing detailed data on disease characteristics and outcomes: Swiss Adult Congenital HEart disease Registry (SACHER). Its aim is to improve the knowledge base of outcomes in adults with CHD. The registry design and baseline patient characteristics are reported. All patients with structural congenital heart defects or hereditary aortopathies, followed-up at dedicated adult CHD clinics, are asked to participate in SACHER. Data of participants are pseudonymised and collected in an electronic, web-based, database (secuTrial®). Collected data include detailed diagnosis, type of repair procedures, previous complications and adverse outcomes during follow-up. From May 2014 to December 2016, 2836 patients (54% male, mean age 34 ± 14 years), with a wide variety of congenital heart lesions, have been enrolled into SACHER. Most prevalent were valve lesions (25%), followed by shunt lesions (22%), cyanotic and other complex congenital heart disease (16%), diseases affecting the right heart, i.e., tetralogy of Fallot or Ebstein anomaly (15%), and diseases of the left ventricular outflow tract (13%); 337 patients (12%) had concomitant congenital syndromes. The majority had undergone previous repair procedures (71%), 47% of those had one or more reinterventions. SACHER collects multicentre data on adults with CHD. Its structure enables prospective data analysis to assess detailed, lesion-specific outcomes with the aim to finally improve long-term outcomes

Predictors of quality of life in young adults with congenital heart disease

Aims: The aim of this study was to identify medical and psychosocial risk factors for impaired health-related quality of life (HRQoL) and poor psychological adjustment (PA) in young adults with congenital heart disease (CHD). Methods and Results: A group of 188 patients (43% females, ages 18-30 years) with various types of CHD and 139 age-matched healthy controls (57% females) completed questionnaires assessing HRQoL, PA, social support, significant life events in the past year, education level, civil status, and employment status. Medical variables were retrieved from the patients' hospital records. Patients reported worse physical HRQoL than controls but similar mental HRQoL and PA. Female CHD patients showed worse physical and mental HRQoL and poorer PA than males. In CHD patients, a lower educational level and lower physical exercise capacity predicted lower physical HRQoL, but complexity of CHD was not related to HRQoL or PA. Less social support was associated with lower mental HRQoL and poorer PA in CHD patients. Conclusion: Young adults with CHD have impaired physical HRQoL but normal mental HRQoL and PA. Lower physical exercise capacity, female sex, less social support and lower educational level predict an unfavorable quality of life and PA. This subgroup of patients should be monitored more closely and provided with special psychosocial care to improve long-term outcome

A Randomized Trial of Rofecoxib for the Chemoprevention of Colorectal Adenomas

BACKGROUND & AIMS: In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas. METHODS: We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline. RESULTS: Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events. CONCLUSIONS: In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity

Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1

Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, theattenuatedgrowth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cell– based vaccine