Targeting antigens to DEC-205 on dendritic cells induces immune protection in experimental colitis in mice

Abstract

The endocytotic c-type lectin receptor DEC-205 is highly expressed on immature dendritic cells. In previous studies, it was shown that antigen-targeting to DEC-205 is a useful tool for the induction of antigen-specific Foxp3+ regulatory T cells and thereby can prevent inflammatory processes. However, whether this approach is sufficient to mediate tolerance in mucosal tissues like the gut is unknown. In this study, we established a new mouse model in which the adoptive transfer of naive hemagglutinin (HA)-specific CD4+Foxp3– T cells into VILLIN-HA transgenic mice leads to severe colitis. To analyze if antigen-targeting to DEC-205 could protect against inflammation of the gut, VILLIN-HA transgenic mice were injected with an antibody–antigen complex consisting of the immunogenic HA110–120 peptide coupled to an α-DEC-205 antibody (DEC-HA) before adoptive T cell transfer. DEC-HA-treated mice showed significantly less signs of intestinal inflammation as was demonstrated by reduced loss of body weight and histopathology in the gut. Strikingly, abrogated intestinal inflammation was mediated via the conversion of naive HA-specific CD4+Foxp3– T cells into HA-specific CD4+Foxp3+ regulatory T cells. In this study, we provide evidence that antigen-targeting to DEC-205 can be utilized for the induction of tolerance in mucosal organs that are confronted with large numbers of exogenous antigens.

Dendritic Cells As Inducers of Peripheral Tolerance

“…In other models of autoimmunity, targeted delivery of specific antigens to DEC205 + DCs led to similar protection from disease. In a VILLIN-HA transgenic mouse model of inflammatory bowel disease (IBD) where HA is expressed in the intestinal epithelium, a delivery of HA to DEC205 + DCs prevented IBD induced by HA-specific T cells [113]. Finally, targeted delivery of proteoglycan (PG) to DEC205 + DCs prevented the subsequent induction of a PG-induced arthritis [114].…”

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease

“…To achieve tolerance, intravenous peptide delivery necessitates the administration of multiple doses, depending on the disease model examined (32)(33)(34). Peptides, proteins, or conjugated peptides (e.g., peptides conjugated to anti-DEC205) delivered systemically do not benefit from specific targeting, as in the case of our sortase-modified RBCs.…”

Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer

“…As these results are unexpected and in part in contrast to the published literature we made use of two other mouse models for colonic inflammation to validate our results. We used the RAG2 -/- T cell transfer colitis model [ 25 ] and the VILLIN-HA T cell transfer model [ 26 ]. Based on our experimental set up, mice were infected with H .…”