Human and murine clonal CD8+ T cell expansions arise during tuberculosis because of TCR selection

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-? production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.This work was supported by the Portuguese Foundation for Science and Technology individual fellowship (CNA) www.fct.pt, a National Institutes of Health Grant R01 AI106725 (SMB) www.nih.gov, and a Center for AIDS Research Grant P30 AI 060354 (SMB) www.nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

EspA Acts as a Critical Mediator of ESX1-Dependent Virulence in Mycobacterium tuberculosis by Affecting Bacterial Cell Wall Integrity

Mycobacterium tuberculosis (Mtb) requires the ESX1 specialized protein secretion system for virulence, for triggering cytosolic immune surveillance pathways, and for priming an optimal CD8+ T cell response. This suggests that ESX1 might act primarily by destabilizing the phagosomal membrane that surrounds the bacterium. However, identifying the primary function of the ESX1 system has been difficult because deletion of any substrate inhibits the secretion of all known substrates, thereby abolishing all ESX1 activity. Here we demonstrate that the ESX1 substrate EspA forms a disulfide bonded homodimer after secretion. By disrupting EspA disulfide bond formation, we have dissociated virulence from other known ESX1-mediated activities. Inhibition of EspA disulfide bond formation does not inhibit ESX1 secretion, ESX1-dependent stimulation of the cytosolic pattern receptors in the infected macrophage or the ability of Mtb to prime an adaptive immune response to ESX1 substrates. However, blocking EspA disulfide bond formation severely attenuates the ability of Mtb to survive and cause disease in mice. Strikingly, we show that inhibition of EspA disulfide bond formation also significantly compromises the stability of the mycobacterial cell wall, as does deletion of the ESX1 locus or individual components of the ESX1 system. Thus, we demonstrate that EspA is a major determinant of ESX1-mediated virulence independent of its function in ESX1 secretion. We propose that ESX1 and EspA play central roles in the virulence of Mtb in vivo because they alter the integrity of the mycobacterial cell wall

Distributive justice and the durability of peace agreements

This study explores the relationship between principles of distributive justice (DJ) and the durability of negotiated agreements. Sixteen peace agreements negotiated during the early 1990s were coded for the centrality of each of four principles of DJ – equality, proportionality, compensation, and need – to the core terms of the agreement. The agreements were also assessed on scales of implementation and durability over a five-year period. Another variable included in the analysis was the difficulty of the conflict environment. These data were used to evaluate three sets of hypotheses: the relationship between DJ and durability, the role of the conflict environment, and types of DJ principles. The results obtained from both statistical and focused-comparison analyses indicate that DJ moderates the relationship between conflict environments and outcomes: when principles of justice are central to an agreement, the negative effects of difficult conflict environments are reduced; when principles are not central, the negative effects of difficulty are heightened. These relationships are accounted for primarily by one of the four DJ principles – equality. Implications of these findings are discussed along with a number of ideas for further research

Diabetic pregnancy and perinatal morbidity

Pregnancy outcome was analyzed in 147 diabetic women, 71 per cent of whom were dependent on insulin for more than 10 years. Ambulatory management of diabetes was carried out with weekly clinic visits until hospitalization at 36 to 37 weeks' gestation. Modern methods of fetal assessment were applied, and the timing and route of delivery were individualized. Of these patients, 35 per cent were delivered at or beyond 38 weeks' gestation. The primary cesarean section rate was 55 per cent. Polyhydramnios was a frequent maternal complication and was associated with premature labor and neonatal death in two cases. Polyhydramnios was least common in women with the lowest mean outpatient blood glucose. The perinatal survival rate was 96.6 per cent, and there were no instances of unexpected intrauterine fetal death. The incidence of respiratory distress syndrome (RDS) in the newborn infant was 7.6 per cent. No severe RDS was seen when the lecithin/sphingomyelin (L/S) ratio was greater than 3.0, but three of 24 infants delivered with an L/S ratio of 2.1 to 3.0 developed severe RDS. Other forms of neonatal morbidity noted in this population were 9 per cent major congenital anomalies; 7 per cent transient tachypnea of the newborn, 22 per cent hypocalcemia, 19 per cent hyperbilirubinemia, and 47 per cent hypoglycemia. The latter was more common in macrosomic infants, defined as greater than the ninetieth percentile of birth weight for gestational age (LGA), who represented 36 per cent of the neonates. Mean outpatient postprandial blood glucose was higher in patients delivered of LGA infants and was correlated with birth weight in White Classes B to D