Mapping the road to peripheral immune tolerance

Immunological tolerance is defined by the unresponsiveness of the host immune system to self-antigens and environmental innocuous antigens, while retaining the capacity to react specifically to countless foreign antigens. This state of immunological unresponsiveness is maintained by a special subset of T cells called regulatory T cells (Treg). Tolerance towards self-derived antigens is mediated by naturally occurring Treg cells, which are generated in the thymus based on self-MHC recognition. In addition to the thymic Treg cells, other types of Treg cells are induced in peripheral lymphoid tissues. Dendritic cells (DCs) are vital in promoting the generation of peripheral Treg cells. Being the most potent antigen presenting cells, DCs are capable of educating naïve T cells into Treg cells. This is achieved by providing tolerogenic cues to the primed naïve T cells. Variations in the DC-derived tolerogenic signals lead to the induction of different types of Treg cells, the most prominent of which are Foxp3+ Treg cells and the IL-10-secreting Tr1 type of Treg cells. It is suggested that those variations can be attributed to differences in the microenvironment, where DCs reside. The microenvironment of certain tissues is dominated by specific components, like vitamin D3 in the skin, and retinoic acid and transforming growth factor (TGF)- in the intestine, which can all affect DC functions. Currently, it remains largely unclear how DCs, under the influence of their microenvironment, can give rise to functionally distinct types of Treg cells that can maintain peripheral tolerance in humans. Therefore, this project aims at defining the tolerogenic print of DCs under the influence of tissue-specific elements, and characterizing the DC-induced, functionally distinct types of Treg cells.