Synthetic 5-amino-6-D-ribitylaminouracil paired with inflammatory stimuli facilitates MAIT cell expansion in vivo.

Introduction: Mucosal-associated invariant T (MAIT) cells are a population of innate-like T cells, which mediate host immunity to microbial infection by recognizing metabolite antigens derived from microbial riboflavin synthesis presented by the MHC-I-related protein 1 (MR1). Namely, the potent MAIT cell antigens, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU), form via the condensation of the riboflavin precursor 5-amino-6-D-ribitylaminouracil (5-A-RU) with the reactive carbonyl species (RCS) methylglyoxal (MG) and glyoxal (G), respectively. Although MAIT cells are abundant in humans, they are rare in mice, and increasing their abundance using expansion protocols with antigen and adjuvant has been shown to facilitate their study in mouse models of infection and disease. Methods: Here, we outline three methods to increase the abundance of MAIT cells in C57BL/6 mice using a combination of inflammatory stimuli, 5-A-RU and MG. Results: Our data demonstrate that the administration of synthetic 5-A-RU in combination with one of three different inflammatory stimuli is sufficient to increase the frequency and absolute numbers of MAIT cells in C57BL/6 mice. The resultant boosted MAIT cells are functional and can provide protection against a lethal infection of Legionella longbeachae. Conclusion: These results provide alternative methods for expanding MAIT cells with high doses of commercially available 5-A-RU (± MG) in the presence of various danger signals.

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries.

Mucosal-associated Invariant T (MAIT) cells recognize vitamin B-based antigens presented by the non-polymorphic MHC class I related-1 molecule (MR1). Both MAIT T cell receptors (TCR) and MR1 are highly conserved among mammals, suggesting an important, and conserved, immune function. For many years, the antigens they recognize were unknown. The discovery that MR1 presents vitamin B-based small molecule ligands resulted in a rapid expansion of research in this area, which has yielded information on the role of MAIT cells in immune protection, autoimmune disease and recently in homeostasis and cancer. More recently, we have begun to appreciate the diverse nature of the small molecule ligands that can bind MR1, with several less potent antigens and small molecule drugs that can bind MR1 being identified. Complementary structural information has revealed the complex nature of interactions defining antigen recognition. Additionally, we now view MAIT cells (defined here as MR1-riboflavin-Ag reactive, TRAV1-2+ cells) as one subset of a broader family of MR1-reactive T cells (MR1T cells). Despite these advances, we still lack a complete understanding of how MR1 ligands are generated, presented and recognized in vivo. The biological relevance of these MR1 ligands and the function of MR1T cells in infection and disease warrants further investigation with new tools and approaches.

A Highly Effective π-π Stacking Strategy To Modify Black Phosphorus with Aromatic Molecules for Cancer Theranostics.

Even though black phosphorus (BP) has exhibited outstanding capabilities in biomedical, physical, and energy fields, the issues of degradation under ambient conditions and unreactive functional interface limit its further application. There are numerous methodologies utilized to prevent BP degradation; however, these methods usually generate further problems and normally do not involve alterations to the chemically inert BP. Herein, for the first time, we propose a simple and efficient strategy to prepare and modify BP nanosheets (p-BPNSs) by employing aromatic 1-pyrenylbutyric acid through a noncovalent π-π stacking interaction. This strategy not only adopts a novel strategy for enhancing the stability of BPNSs but also paves a convenient way to anchor other active biomolecules such as a targeting effect to extend the biomedical applications of BPNSs. The modified p-BPNSs exhibit enhanced physical and chemical stabilities as well as rich carboxyl groups for further modification. In this work, RGD-modified p-BPNSs exhibit targeted photothermal therapy ability against cancer in both in vitro and in vivo studies, owing to anchoring of arginine-glycine-aspartic acid (RGD) tripeptides, which could target nanosheets into the tumor site through systematic circulation. Consequently, this work not only provides a new concept for modifying and protecting the BP but also opens a novel window for extending the biomedical application of BP by surface engineering.

A black phosphorus nanosheet-based siRNA delivery system for synergistic photothermal and gene therapy.

Gene therapy with small interfering RNA (siRNA) has been proved to be a promising technology to treat various diseases by hampering the production of target proteins. However, developing a delivery system that has high efficiency in transporting siRNA without obvious side effects remains a challenge. Herein, we designed a new survivin siRNA delivery system based on polyethyleneimine functionalized black phosphorus (BP) nanosheets which could suppress tumor growth by silencing survivin expression. Combined with the photothermal properties of the BP nanosheets, the presented delivery system shows excellent therapy efficiency for tumors. Therefore, the BP-based delivery system would be a promising tool for future clinical applications.