The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as “trained immunity.” Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a “trained” state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.

Dendritic cells (DCs) are professional APCs with the unique ability to activate naive T cells, which is required for initiation of the adaptive immune response against pathogens. Therefore, interfering with DC function would be advantageous for pathogen survival and dissemination. In this study we provide evidence suggesting that Salmonella enterica serovar typhimurium, the causative agent of typhoid disease in the mouse, interferes with DC function. Our results indicate that by avoiding lysosomal degradation, S. typhimurium impairs the ability of DCs to present bacterial Ags on MHC class I and II molecules to T cells. This process could correspond to a novel mechanism developed by this pathogen to evade adaptive immunity. In contrast, when S. typhimurium is targeted to FcγRs on DCs by coating bacteria with Salmonella-specific IgG, bacterial Ags are efficiently processed and presented on MHC class I and class II molecules. This enhanced Ag presentation leads to a robust activation of bacteria-specific T cells. Laser confocal microscopy experiments show that virulent S. typhimurium is rerouted to the lysosomal degradation pathway of DCs when internalized through FcγR. These observations are supported by electron microscopy studies demonstrating that internalized S. typhimurium shows degradation signs only when coated with IgG and captured by FcγRs on DCs. Therefore, our data support a potential role for bacteria-specific IgG on the augmentation of Ag processing and presentation by DCs to T cells during the immune response against intracellular bacteria.

Respiratory syncytial virus (RSV) infection isimmunological synapse ͉ virus evasion ͉ virulence mechanism ͉ adaptive immunity R espiratory syncytial virus (RSV) is the worldwide leading cause of infant hospitalization related to airway diseases. RSV infects Ͼ70% of children in the first year of life and by age 2, almost 100% of children have been infected at least once with this virus (1, 2). In addition, RSV reinfection is extremely frequent, suggesting that naturally acquired adaptive immunity to RSV is either inefficient or transient (2-4). It is thought that clearance of RSV would require the induction of a balanced Th1/Th2 adaptive immune response capable of inducing the production of neutralizing antibodies and IFN-␥-secreting cytotoxic CD8 ϩ T cells (CTLs) (5, 6). However, RSV-specific T cell responses generally fail to efficiently clear infection (7-9). Although functional RSV-specific memory CTLs and helper T cells can be observed in the blood and spleens of infected hosts, these cells show impaired effector function in infected lung tissues (10)(11)(12)(13)(14).Dendritic cells (DCs) are ubiquitous professional antigenpresenting cells (APCs) found in lymphoid and nonlymphoid tissues, where they locate strategically to capture antigens and present them to T cells as peptides bound to either MHC class I or II molecules (15, 16). These features render DCs as key components for the initiation and modulation of T cell immunity against pathogens, such as virus. Thus, several virulent microorganisms have developed molecular mechanisms to impair DC function and prevent clearance by adaptive immunity (17-21). RSV infection causes a significant increase in the number of mature DCs in mouse lungs (22,23) and has the capacity to infect and replicate within these cells (24-27), rendering them inefficient at inducing proliferation and IFN-␥ secretion by antigenspecific T cells (24,25). Inhibition of T cell activation by RSV has been suggested to be mediated by soluble molecules secreted by RSV-infected DCs, which reduce their capacity to induce IFN-␥ secretion by T cells (28). Although recent data indicate that RSV-induced secretion of IFN-and -␣ by human DCs can impair T cell activation (29), this phenomenon could also be observed upon T cell culture with RSV particles or cells expressing RSV antigens on their surface (30, 31). However, whether RSV-mediated inhibition applies to cognate pMHC recognition by T cells and the mechanism responsible for this inhibition remain unknown.Here, we have approached these questions by evaluating the effect of RSV infection on the capacity of murine DCs to activate T cells. We observed that DCs are efficiently infected by RSV and, although these cells mature upon infection, they are rendered unable to promote T cell activation in response to cognate-, allo-, and superantigen stimuli. Upon exposure to RSV-infected DCs, T cell proliferation and IL-2 secretion were significantly impaired, and T cells became unresponsive to subsequent stimulation with anti-CD3. Inhibition was not medi...

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Respiratory syncytial virus (RSV) is

Specialized transduction has proven to be useful for generating deletion mutants in most mycobacteria, including virulent Mycobacterium tuberculosis. We have improved this system by developing (i) a single-step strategy for the construction of allelic exchange substrates (AES), (ii) a temperature-sensitive shuttle phasmid with a greater cloning capacity than phAE87, and (

CD8 ؉ T cells recognize peptides of eight to nine amino acid residues long in the context of MHC class I molecules on the surface of antigen-presenting cells (APCs). This recognition event is highly sensitive, as evidenced by the fact that T cells can be activated by cognate peptide͞MHC complex (pMHC) at extremely low densities (1-50 molecules). High sensitivity is particularly valuable for detection of antigens at low density, such as those derived from tumor cells and intracellular pathogens, which can down-modulate cognate pMHCs from the surface of APCs to evade recognition by the adaptive immune system. T cell activation is only triggered in response to interactions between the T cell receptor (TCR) and the pMHC ligand that reach a specific half-life threshold. However, interactions with excessively long half-lives result in impaired T cell activation. Thus, efficient T cell activation by pMHC on the surface of APCs requires an optimal dwell time of TCR-pMHC interaction. Here, we show that, although this is a requirement at low cognate pMHC density on the APC surface, at high epitope density there is no impairment of T cell activation by extended TCR-pMHC dwell times. This observation was predicted by mathematical simulations for T cell activation by pMHC at different densities and supported by experiments performed on APCs selected for varied expression of cognate pMHC. According to these results, effective T cell activation depends on a complex interplay between inherent TCR-pMHC binding kinetics and the epitope density on the APC.

Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD−/+gD−1). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD−/+gD1 provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD−/+gD1 elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.DOI: http://dx.doi.org/10.7554/eLife.06054.001