Polyfunctional CD4+ T Cells As Targets for Tuberculosis Vaccination

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of morbidity and mortality worldwide, despite the widespread use of the only licensed vaccine, Bacille Calmette Guerin (BCG). Eradication of TB will require a more effective vaccine, yet evaluation of new vaccine candidates is hampered by lack of defined correlates of protection. Animal and human studies of intracellular pathogens have extensively evaluated polyfunctional CD4+ T cells producing multiple pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2) as a possible correlate of protection from infection and disease. In this study, we review the published literature that evaluates whether or not BCG and/or novel TB vaccine candidates induce polyfunctional CD4+ T cells and if these T cell responses correlate with vaccine-mediated protection. Ample evidence suggests that BCG and several novel vaccine candidates evaluated in animal models and humans induce polyfunctional CD4+ T cells. However, while a number of studies utilizing the mouse TB model support that polyfunctional CD4+ T cells are associated with vaccine-induced protection, other studies in mouse and human infants demonstrate no correlation between these T cell responses and protection. We conclude that induction of polyfunctional CD4+ T cells is certainly not sufficient and may not even be necessary to mediate protection and suggest that other functional attributes, such as additional effector functions, T cell differentiation state, tissue homing potential, or long-term survival capacity of the T cell may be equally or more important to promote protection. Thus, a correlate of protection for TB vaccine development remains elusive. Future studies should address polyfunctional CD4+ T cells within the context of more comprehensive immunological signatures of protection that include other functions and phenotypes of T cells as well as the full spectrum of immune cells and mediators that participate in the immune response against Mtb

TRAV1-2(+) CD8(+) T-cells including oligoconal expansions of MAIT cells are enriched in the airways in human tuberculosis

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2(+) semi-invariant TCRalpha that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2(+) CD8(+) T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2(+) MAIT-consistent TCRalpha sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial reactivity and phenotypes suggestive of MAIT cell identity. These findings demonstrate enrichment of TRAV1-2(+) CD8(+) T cells with MAIT or MAIT-like features in the airways during active TB and suggest a role for these cells in the human pulmonary immune response to Mycobacterium tuberculosis

Species richness in natural and disturbed habitats: Asteraceae and Flower-head insects (Tephritidae: Diptera)

Anthropogenic changes in the landscape result in an environmental mosaic with serious consequences for biodiversity. The aim of the present study was to assess the effects of the anthropogenic changes on Asteraceae richness and abundance, and to evaluate the consequences for the richness of Tephritidae assemblages in five sampling sites, with three sampled habitats in each: cerrado (Brazilian savanna), eucalyptus stands and pasture. Sampling was carried out in 15 random transects (cerrados and one pasture) and in 30 transects (eucalyptus stands and the remaining pastures). Composition, species richness and insect abundance in each habitat type was estimated by sampling the flower heads for each species of host plant, collected by four people for 1h. Differences in mean abundance of plant population between habitats and sites were tested by two-way ANOVA. Differences in plant species richness between habitats and sites and effects of habitat, site and host plant richness on insect richness were tested using a generalized linear model with Poisson errors. Within each sampling site, cerrados showed higher species richness of Asteraceae than pastures and eucalyptus stands. There were also significant differences in plant richness among sites. Mean population abundance values were significantly different among habitats, but not among sites. Increased host plant richness led to significant insect species richness. There were no additional significant effects of habitat on insect richness. Therefore, anthropogenic alterations in landscape determined the impoverishment of plant assemblages and therefore of insect assemblages, because of the positive relationship between host plant richness and insect richness.163171Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Escape from the Phagosome: The Explanation for MHC-I Processing of Mycobacterial Antigens?

Mycobacterium tuberculosis (Mtb) is thought to live in an altered phagosomal environment. In this setting, the mechanisms by which mycobacterial antigens access the major histocompatibility class I (MHC-I) processing machinery remain incompletely understood. There is evidence that Mtb antigens can be processed in both endocytic and cytosolic environments, with different mechanisms being proposed for how Mtb antigens can access the cytosol. Recently, electron microscopy was used to demonstrate that Mtb has the potential to escape the phagosome and reside in the cytosol. This was postulated as the primary mechanism by which Mtb antigens enter the MHC-I processing and presentation pathway. In this commentary, we will review data on the escape of Mtb from the cytosol and whether this escape is required for antigen presentation to CD8+ T cells

Involvement of A pertussis Toxin Sensitive G-Protein in the Inhibition of Inwardly Rectifying K+ Currents by Platelet-Activating Factor in Guinea-Pig Atrial Cardiomyocytes

Platelet-activating factor (PAF) inhibits single inwardly rectifying K+ channels in guinea-pig ventricular cells. There is currently little information as to the mechanism by which these channels are modulated. The effect of PAF on quasi steady-state inwardly rectifying K+ currents (presumably of the IK1 type) of auricular, atrial and ventricular cardiomyocytes from guinea-pig were studied. Applying the patch-clamp technique in the whole-cell configuration, PAF (10 nM) reduced the K+ currents in all three cell types. The inhibitory effect of PAF occurred within seconds and was reversible upon wash-out. It was almost completely abolished by the PAF receptor antagonist BN 50730. Intracellular infusion of atrial cells with guanine 5′-(β-thio)diphosphate (GDPS) or pretreatment of cells with pertussis toxin abolished the PAF dependent reduction of the currents. Neither extracellularly applied isoproterenol nor intracellularly applied adenosine 3′,5′-cyclic monophosphate (cyclic AMP) attenuated the PAF effect. In multicellular preparations of auricles, PAF (10 nM) induced arrhythmias. The arrhythmogenic activity was also reduced by BN 50730. The data indicate that activated PAF receptors inhibit inwardly rectifying K+ currents via a pertussis toxin sensitive G-protein without involvement of a cyclic AMP-dependent step. Since IK1 is a major component in stabilizing the resting membrane potential, the observed inhibition of this type of channel could play an important role in PAF dependent arrhythmogenesis in guinea-pig heart