PLGA nanoparticles enhance the expression of retinaldehyde dehydrogenase enzymes in dendritic cells and induce FoxP3(+) T-cells in vitro

Many autoimmune diseases and other chronic inflammatory disorders are characterized by defective FoxP3+ regulatory T-cell (Treg) mediated suppression. A potential treatment option for these disorders is to increase the number and activity of Tregs locally. Both PLGA (poly-lactic-co-glycolic acid) and TMC-TPP (N-trimethyl chitosan tripolyphosphate) nanoparticles (NP) have been described to enhance T cell activation upon nasal application. Since, PLGA NP and TMC-TPP NP differentially affect CD4+ T-cell differentiation, we investigated in vitro the capacity of both delivery systems to trigger retinoic acid (RA) production in dendritic cells (DCs) as a strategy to enhance the induction of FoxP3+ T-cells. We generated ovalbumin (OVA)-encapsulated PLGA NP and TMC-TPP NP that were similar in size (400 nm) but differed in their surface charge and other physico-chemical properties. We demonstrate that OVA-specific T-cells that are activated by cervical lymph node (CLN)-derived DCs treated with PLGA NP or TMC-TPP NP show more FoxP3 expression than T-cells that are activated by inguinal lymph node (ILN) cells. We demonstrate that only OVA-encapsulated PLGA NP enhance the induction of FoxP3 in activated T-cells via a TGF-β and RA dependent mechanism by enhancing retinaldehyde dehydrogenase enzyme (RALDH) expression in CLN-derived DCs that is required for RA production. Additionally, detailed analysis of the CD4+ T-cell response reveals that PLGA NP induce both IL-10 and IFN-γ production, while TMC-TPP NP induce mainly Th17 production. Underlining that both APC origin and NP characteristics determine the expression level of FoxP3 in activated T-cells. In conclusion, our data suggest that PLGA NP enhance the induction of FoxP3+ T-cells in the CLN through modulation of DC function and we suggest that they might be a suitable nasal delivery system to treat a wide variety of autoimmune diseases and other chronic inflammatory disorders.