The aryl-hydrocarbon receptor (AhR) is an important receptor found in immune cells. Itfunctions as a detector of environmental toxins, naturally occurring dietary products, andendogenous tryptophan derivatives for induction of gene transcription responses. Previousreports have implicated stimulation of AhR by various ligands in promoting T cellactivation or regulatory function, with effects on autoimmune disease models. Also, effectsof Ah toxins or natural products on increasing or suppressing inflammation and innatecytokine production, and dendritic cell function, have been reported. Different AhR-ligandscould help in the development of either regulatory or pro-inflammatory T cells andconsequently affect autoimmunity. In the present study, the effects of specific AhR-ligandson CD4 T cells, BMDC and CD8 T cells were investigated. Their effects were also testedfor the first time on the induction of autoimmune diabetes using two different mousemodels. Co-injection of the AhR-ligands curcumin, quercetin, or the ligand precursortryptophan with sub-diabetogenic multiple low dose streptozotocin (MLD-STZ), increasedthe incidence of hyper-glycemia in C57Bl/6J mice. Furthermore, these ligands were able tosignificantly increase the development of Th17 and Th1 subsets and suppress Treg cells, invivo and in vitro. In contrast, other ligands, including FICZ and I3C, decreased theincidence of diabetes in the MLD-STZ mouse model, in addition to their ability to increasethe development of Th17, Th1 and Treg subsets, in vivo and in vitro. We found thatinjecting gp130fl/flCD4-Cre+ mice, which are characterized by enhanced production of Tregand reduced Th17 cell development, with MLD-STZ failed to cause hyper-glycemia,suggesting that the IL-6-receptor pathway controlling the Th17/Treg cell balance isimportant for diabetes induced by MLD-STZ. The effect of tryptophan, curcumin orquercetin was also tested for the first time using the RIP-LCMV-GP / P14 TCR transgenicdiabetes model. We find that co-injection of these ligands together with immunisation withmature bone marrow-derived dendritic cells (BMDC) carrying self-antigen increased theincidence of diabetes in RIP-GP/P14 TCR transgenic mice. Also, these AhR-ligands wereable to significantly increase Tc17 and Tc1 cell subsets, in vitro and in vivo. Furthermore,these ligands were able to increase the secretion of both pro-inflammatory, antiinflammatorycytokines, and the expression of IDO by BMDC. FICZ and I3C, however,increased the expression of IDO and the anti-inflammatory cytokines TGF-β and IL-10. Animmuno-suppressive function of FICZ and I3C was confirmed by co-injection of theseAhR-ligands together with immunisation with mature BMDC carrying self-antigen, whichresulted in a decrease in the incidence of diabetes in RIP-GP/P14 TCR transgenic mice.Suppression of diabetes was associated with increased development of IL-10+ CD8+ T cells,in vitro, while having no significant effect on either Tc1 or Tc17 subsets. It is concludedfrom this study that, the AhR-ligands FICZ and I3C could be attractive compounds to beused as therapeutics for diabetes and other autoimmune diseases, due to their ability toincrease regulatory T cells (Treg and IL-10+ CD8+ ) subsets and enhance the secretion ofanti-inflammatory cytokines and IDO expression by BMDC. However, activation of theAhR pathway by other AhR-ligands is associated with increased Th1/Tc1 and Th17/Tc17responses, which could worsen autoimmunity.
|Date of Award
|1 Aug 2012
- The University of Manchester
|Douglas Millar (Supervisor) & Kathryn Else (Supervisor)