Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation

Abstract

Synthetic glycine coated 50 nm polystyrene nanoparticles (NP) (PS50G), unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg) in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2) expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis.

Emerging Role of Immunosuppression in Diseases Induced by Micro- and Nano-Particles: Time to Revisit the Exclusive Inflammatory Scenario

“…Recent results indicated that T regs are progressively and specifically accumulated in lung tissue of mice treated with silica where they promote pulmonary immunosuppression and fibrosis ( 58 , 60 ) (Figure 2 ). This hallmark of immunological tolerance and immunosuppressive environment was observed with other particles, detected locally and systemically, and induced by the Wnt/B-catenin pathway ( 57 , 59 , 97 , 98 ). Lung T regs directly stimulated fibroblast proliferation and collagen deposition after transfer in non-treated mice ( 58 ).…”

“…CNT induce the expression of TGF-β and IL-10 ( 57 ) as observed for micrometric silica (see above). Nanoparticles also facilitate polarization of immunosuppressive T regs and anti-inflammatory Th2 lymphocytes ( 98 , 123 , 124 ). Mechanistic studies investigating the effects of nanoparticles on T-lymphocyte immunosuppressive lineage commitment revealed that nanoparticles (carbon, grapheme, and iron) directly interfere with autophagy, ROS production, NFκB-nuclear translocation or antigen processing by dendritic cells ( 124 – 126 ).…”

The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review

“…Previously, it was shown that TNFR2 maintains adequate IL-12 production by DCs in inflammatory responses by regulating endogenous TNF level ( 91 ). In addition, selective expansion of maximally suppressive TNFR2 + Foxp3 + Tregs in pulmonary inflammation can be induced by engineered nanoparticles through the activation of CD103 + DCs ( 92 ).…”

“…Nanoparticles, with their various immunological effects in the lung ( 109 ), can be utilized to selectively block TNFR1 and/or activate TNFR2. A synthetic nanoparticle has been used to imprint innate immunity when pre-exposed mice preferentially expanded TNFR2 + Foxp3 + Tregs after allergen challenge, partly via the activation of CD103 + DCs ( 92 , 110 ). This non-toxic engineered nanoparticle evidenced the selective modulation of Tregs homeostasis through mechanisms such as maintenance of TNF-TNFR2 interaction, targeting CD103 + DCs, and expanding the proliferative rate of Tregs, thus decreasing the susceptibility to allergic disease.…”

Synergistic Effects of Nanomedicine Targeting TNFR2 and DNA Demethylation Inhibitor—An Opportunity for Cancer Treatment

“…Despite the emerging trends of using nanoparticles in immunotherapy, no studies have investigated any type of nanocarriers to target TNFR2 on cancer cells. However, based on some previous novel reports about the effects of nanoparticles on immune homeostasis [13], especially using nanoparticles to promote TNFR2 + Foxp3 + regulatory T cells (Tregs) in inflammatory models [14,15], we have suggested in our recent perspective review the possibility of blocking TNF-TNFR2 axis via nanoparticles [16].…”