Regulatory T cells (Tregs) are indispensable for the control of immune homeostasis and have clinical potential as a cell therapy for treating autoimmunity. Tregs can lose expression of the lineage-defining Foxp3 transcription factor and acquire effector T cell (Teff) characteristics, a process referred to as Treg plasticity. The extent and reversibility of such plasticity during immune responses remain unknown. Here, using a murine genetic fate-mapping system, we show that Treg stability is maintained even during exposure to a complex microbial/antigenic environment. Furthermore, we demonstrate that the observed plasticity of Tregs after adoptive transfer into a lymphopenic environment is a property limited to only a subset of the Treg population, with the nonconverting majority of Tregs being resistant to plasticity upon secondary stability challenge. The unstable Treg fraction is a complex mixture of phenotypically distinct Tregs, enriched for naïve and neuropilin-1–negative Tregs, and includes peripherally induced Tregs and recent thymic emigrant Tregs. These results suggest that a “purging” process can be used to purify stable Tregs that are capable of robust fate retention, with potential implications for improving cell transfer therapy.
FOXP3-expressing regulatory T cells (T reg ) are indispensable for immune homeostasis and tolerance, and in addition tissue-resident T reg have been found to perform noncanonical, tissue-specific functions. For optimal tolerogenic function during inflammatory disease, T reg are equipped with mechanisms that assure lineage stability. T reg lineage stability is closely linked to the installation and maintenance of a lineage-specific epigenetic landscape, specifically a T regspecific DNA demethylation pattern. At the same time, for local and directed immune regulation T reg must possess a level of functional plasticity that requires them to partially acquire T helper cell (T H ) transcriptional programsthen referred to as T H -like T reg . Unleashing T H programs in T reg , however, is not without risk and may threaten the epigenetic stability of T reg with consequently pathogenic ex-T reg contributing to (auto-) inflammatory conditions. Here, we review how the T reg -stabilizing epigenetic landscape is installed and maintained, and further discuss the development, necessity and lineage instability risks of T H 1-, T H 2-, T H 17-like T reg and follicular T reg .
Diseases caused by Dengue (DENV) and Zika (ZIKV) viruses cause significant mortality and illness globally. Due to the high sequence similarity of the viral proteins and the purported cross-reactive immune responses against the viruses, we envisioned a common multi-epitope vaccine (MEV) against both viruses by adopting a novel approach of identifying “immunogenic hotspots”. These stretches of the structural and non-structural proteins are enriched with MHC class I and class II supertype-restricted T cell epitopes, and B cell epitopes, in addition to being highly conserved between different DENV serotypes and ZIKV. Such an approach ensures inclusion of multiple overlapping T and B cell epitopes common to both viruses, and also warrants high population coverage. Importantly, epitopes known to cause antibody-dependent-enhancement of infection have been excluded. These immunogenic hotspots have then been stitched together with linkers in-silico along with an adjuvant, CTxB to develop the MEV candidate. Four structural models of the MEV were selected on the basis of conformational preservation of CTxB, and their biophysical parameters, which also conserved the immunogenicity of the multiple epitopes. Importantly, each of the MEV candidates were found to interact with TLR4-MD2 complex by molecular docking studies, indicative of their ability to induce TLR-mediated immune responses.
Aim: Dengue and Zika viruses cause significant mortality globally. Considering high sequence similarity between the viral proteins, we designed common multi-epitope vaccine candidates against these pathogens. Methods: We identified multiple T and B cell epitope-rich conserved ‘immunogenic hotspots’ from highly antigenic and phylogenetically related viral proteins and used these to design the multi-epitope vaccine (MEV) candidates, ensuring high global population coverage. Results: Four MEV candidates containing conserved immunogenic hotspots from E and NS5 proteins with the highest structural integrity could favorably interact with TLR4-MD2 complex in molecular docking studies, indicating activation of TLR-mediated immune responses. MEVs also induced memory responses in silico, hallmarks of a good vaccine candidate. Conclusion: Conserved immunogenic hotspots can be utilized to design cross-protective MEV candidates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.