Reversal of peanut anaphylaxis by retinoic acid-differentiated dendritic cell immunotherapy. IL-27-dependent induction of Foxp3- non-Tr1 regulatory T cells (VAC4P.1100)

Abstract

Background. Semi-mature IL-10-induced DC (DC10) induce human or mouse effector Th2 cells (Teff) to differentiate into Foxp3+ Treg and thereby induce asthma tolerance. Retinoic acid (RA) and TGFβ-induced gut DC similarly induce tolerance to gut contents via Foxp3+ Treg, while immature hDC-10 induce IL-10-dependent Foxp3- Tr1 cells. Methods. We assessed the abilities of mature RA-induced DC to reverse anaphylaxis sensitivity, characterizing LPS-matured DC-RA and their tolerogenic activities in mouse models of OVA and peanut systemic anaphylaxis. Results. Mature DC-RA strongly expressed CD103 (αE integrin), MHCII, co-stimulatory markers, PDL1 & -L2, ICOSL, TGFβ, IL-27 and the RA-metabolizing enzyme Aldh1A2. They induced Th2 cells to convert into CD25+LAG3+CD49b-IL-10-Foxp3- Treg in an IL-10-independent, IL-27-dependent fashion, although IL-27 was dispensable for Th2 suppression by DC-RA. Wild-type, but not IL-27-/- DC-RA therapy reversed systemic anaphylaxis, including clinical scores, diarrhea, mast cell activation and Th2 responses, and lowered serum allergen-specific IgE and IgG1 levels. Conclusions. Allergen-presenting DC-RA induce food allergen tolerance by activating CD25+Foxp3-, non-Tr1 responses in an IL-27-dependent fashion. This data indicates that, like DC10, DC-RA can also be used for allergic disease immunotherapy, but that these two populations of DCreg induce distinct Treg responses, and this potentially provides us with important options DCreg immunotherapy