Our research focuses on the role of dendritic cells (DCs) and regulatory T cells (Tregs) in peripheral T cell tolerance induction, and how these mechanisms are altered or deficient in an autoimmune setting. DCs are specialized antigen-presenting cells that help determine the type of immune response that develops. Tregs are a subset of CD4 T cells that can inhibit immune responses and help induce tolerance.
Specifically, we are studying immune tolerance in the nonobese diabetic (NOD) mouse, a model of type 1 diabetes: a human T cell-mediated, organ-specific autoimmune disease in which overactive T cell responses to self-antigens expressed in the pancreatic islets cause destruction of insulin-producing beta cells. One long-term goal of our research is to learn how to use DCs to induce autoantigen-specific tolerance for treatment of human type 1 diabetes. Below are outlined some of the areas on which we are now focusing.
Use of steady-state DCs to enhance tolerance via anergy or deletion
If antigens are presented in the context of inflammatory signals such as toll-like receptor ligands, DCs can be activated and the result is immunity; if antigens are presented to T cells in the absence of such signals, i.e., “steady-state,” tolerance results. However, little is known about how this type of tolerance is altered in autoimmune individuals, and if it is possible to induce steady-state tolerance in the environment of chronic autoimmune inflammation.
In order to study DC-mediated, steady-state tolerance in the context of autoimmunity, we are targeting islet autoantigens directly to DCs in vivo via antibodies against endocytic receptors expressed by DCs. In vivo targeting allows one to study dendritic cell function without isolating the DCs, a process that can alter the maturation state of the DCs. We are now comparing the effects of targeting autoantigens to CD8 and CD11b cDCs as well as pDCs.
Plasmacytoid dendritic cells (pDCs) in NOD mice
pDCs are a rare subset of dendritic cells that produce IFN-alpha in response to innate immune signals, but can also present antigen-like conventional DCs. Published reports on the role of pDCs in autoimmunity are mixed. IFN-alpha production can be pro-inflammatory, yet pDCs can also play a tolerogenic role by, for example, inducing Tregs. We are now measuring pDC function in NOD mice compared to control strains.
The role of IL-2 for DC development and function
IL-2, a susceptibility gene for both mouse and human autoimmune diabetes, is important for maintaining immune tolerance via effects on regulatory T cells. However, little is known about how IL-2 affects DCs. We have shown that NOD mice, which have lower IL-2 levels compared to nondiabetic control strains, have higher numbers of pDCs in the spleen. We also showed that IL-2 inhibits both pDC and cDC development, by using in vitro cultures of bone marrow cells stimulated to differentiate with the growth factor Flt3L. Furthermore, DCs developed in the presence of IL-2 displayed decreased ability to stimulate T cells. Our results show that IL-2, in addition to affecting lymphocytes, can modulate DC development and function.