Orally delivered colonization factor antigen I (CFA/I) fimbriae stimulate IL-35 producing Foxp3+CD39+CD4+ regulatory T cells (Tregs) essential against CIA in C57BL/6 mice. To begin to understand how CFA/I-induced IL-35 mediates protection, recent studies have begun to examine immunosuppressive mediators by dendritic cells (DCs). It was found that IDO was induced in splenic, mesenteric lymph nodes (MLNs), and inguinal, axillary, and iliac lymph nodes (LNs) DCs in protected mice. We hypothesize that CFA/I-induced IL-35 could directly regulate development of IDO+ DCs to sustain anti-inflammatory responses. By flow cytometry, recombinant IL-35 was found capable of binding DCs in vitro suggesting direct action of IL-35 upon DCs. Mice deficient in IL-35 (EBI3-/-) were unresponsive to CFA/I fimbriae and unable to induce IDO. Similar results were observed in CD39-/- mice correlating with the lack of clinical interventions. To inhibit IL-35's impact, CFA/I- or PBS-dosed C57BL/6 mice were treated in vivo with rabbit IgG anti-mouse IL-35 during arthritis manifestation resulting in 50% suppression of intracellular IDO expression along with significantly enhanced CIA severity when compared to nonimmune IgG-treated mice. Adoptive transfer of CFA/I-induced CD39+CD4+ Tregs to mice induced with CIA elevated IDO expression by DCs. Thus, our findings demonstrate the effect of induced IL-35 by Tregs upon IDO+ DCs in conferring protection against CIA. Supported by NIH P01 AT-04986.
- Copyright © 2013 by The American Association of Immunologists, Inc.