Specialized role of migratory dendritic cells in peripheral tolerance induction

Abstract

Harnessing DCs for immunotherapies in vivo requires the elucidation of the physiological role of distinct DC populations. Migratory DCs traffic from peripheral tissues to draining lymph nodes charged with tissue self antigens. We hypothesized that these DC populations have a specialized role in the maintenance of peripheral tolerance, specifically, to generate suppressive Foxp3 + Tregs. To examine the differential capacity of migratory DCs versus blood-derived lymphoid-resident DCs for Treg generation in vivo, we targeted a self antigen, myelin oligodendrocyte glycoprotein, using antibodies against cell surface receptors differentially expressed in these DC populations. Using this approach together with mouse models that lack specific DC populations, we found that migratory DCs have a superior ability to generate Tregs in vivo, which in turn drastically improve the outcome of experimental autoimmune encephalomyelitis. These results provide a rationale for the development of novel therapies targeting migratory DCs for the treatment of autoimmune diseases.

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

“…1C, 1D). This observation is consistent with previous studies (25) in that high steady-state expression levels of DEC205 (Supplemental Fig. 1A) correlate with the preferential uptake of the anti-DEC205 Ab in vivo (Supplemental Fig.…”

“…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.…”

“…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.…”

Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity

“…Indeed, DC-based therapy has been proposed to restore tolerance in the context of several autoimmune diseases (20)(21)(22). The two main strategies developed are the direct targeting of Ags to + steady state DCs (11,(23)(24)(25)(26) and the repetitive injection of tolerogenic DCs (27)(28)(29). We have previously demonstrated that repetitive injection of immature and semimature DCs can prevent adverse clinical outcome and protect mice from experimental collagen-induced arthritis (CIA) (30,31).…”

Mesenchymal stem cells for kidney transplantation

“…Secondly, and of relevance to transplantation, they aid in peripheral tolerance. They do this by the presentation of antigens while lacking the co-stimulatory molecules required for T cell activation [32,33] . This causes T cell unresponsiveness as well as Treg induction [33] .…”