Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination

Abstract

■ AbstractDendritic cells (DCs) and Foxp3-expressing CD4 + regulatory T (Treg) cells play non-redundant roles in the maintenance of peripheral tolerance to self-antigens, thereby preventing fatal autoimmunity. A common hallmark of intra-and extrathymic Treg cell lineage commitment is the induction of Foxp3 expression as a consequence of appropriate T cell receptor engagement with MHC class II:agonist ligand. It has now become increasingly clear that agonist ligand presentation by immature DCs in the steady state induces T cell tolerance by both recessive and dominant mechanisms, rather than promoting productive T helper cell responses. In this context, the ability of steady-state DCs to promote the extrathymic conversion of initially naïve CD4 + Foxp3 -T cells into Foxp3 + Treg cells is of particular interest as it provides novel perspectives to enhance antigen-specific Treg cell function in clinical settings of unwanted immunity, such as β-cell autoimmunity.

DEC205+ Dendritic Cell–Targeted Tolerogenic Vaccination Promotes Immune Tolerance in Experimental Autoimmune Arthritis

“…Recombinant anti-DEC205 Abs fused to disease-relevant autoantigens have been developed and used successfully for tolerogenic protection in autoimmune disease models, including autoimmune diabetes (24,26) and EAE (14,18,25). In the present study, we show that administration of a single dose of recombinant anti-DEC205 Ab fused to the cartilage-derived immunodominant PG 70-84 efficiently ameliorates the severity of PG-induced arthritis.…”

“…Additionally, previous studies indicated that DEC205 + DC targeting of self-antigen alone might not be sufficient to interfere with ongoing autoimmune responses (17,18). In this context, the combination of DEC205-targeted self-antigen with other immunomodulatory strategies (e.g., transient coadministration of immunosuppressive drugs) may represent a particularly promising and safe approach to bring tolerogenic DEC205 + DC targeting in human autoimmunity within reach (24,48).…”

“…1A-D). Previous studies in TCR non-transgenic mouse models of autoimmune diabetes (17) and encephalomyelitis (18) established that the induction of immune tolerance by DEC205 + DC-targeted self-antigen critically depends on the administration of anti-DEC205 fusion Abs under subimmunogenic conditions (i.e., low Ag dose, limited T cell costimulation, steady-state DCs) (24,40). Therefore, our studies on DEC205 + DC targeting in PGIA focused on single low-dose administration of the anti-DEC205-PG Ab prior to the induction of PGIA by immunization with whole PG protein and DDA, a potent adjuvant that exerts a strong stimulatory effect via activation of innate immune cells, including DCs (39).…”

“…In contrast, administration of anti-DEC205 Abs that lacked the fusion Ag or had been fused to an irrelevant T cell epitope did not (19,20), indicating that this approach indeed induced Ag-specific alterations in T cell populations. Moreover, coadministration of recombinant anti-DEC205 fusion Abs with adjuvant induced protective immune responses in experimental settings of cancer (21,22) and infection (22,23), further demonstrating that steadystate DCs (i.e., immature DCs with low expression levels of costimulatory molecules) are a prerequisite for the induction of DEC205 + DC-targeted T cell tolerance (20,24). Recombinant anti-DEC205 Abs fused to a T cell-relevant selfantigen can prevent autoimmunity via interference with pathological T cell responses, both through dominant and recessive tolerance mechanisms.…”

“…DEC205 + DC-targeted dominant tolerance can be achieved by the Ag-specific enhancement of Foxp3 + regulatory T cell (Treg) activity (15-18, 24, 25), whereas recessive tolerance mechanisms include deletion and induction of anergy in pathogenic T cells (13,14,18,24). DEC205 + DC targeting has been shown to promote immune tolerance in the spontaneous NOD mouse model of autoimmune diabetes (24,26) and peptide-induced mouse models of experimental autoimmune encephalomyelitis (EAE) (14,18,25). Compared to peptide-induced autoimmune models such as EAE, PGIA is fundamentally different because disease is induced with whole protein, namely human cartilage-derived PG.…”