Cutaneous immune responses must be tightly controlled to prevent inflammatory and allergic diseases, i.e., atopic dermatitis, psoriasis, contact dermatitis, and pemphigus vulgaris. Foxp3+ regulatory T cells (T regs) play a critical role in skin immunoregulation. T regs can be naturally generated in the thymus, or can be induced de nova from CD4+ nave T cells in the periphery by antigen presenting cells, especially dendritic cells (DCs). The DC system is intricate and is comprised of distinct subsets such as skin migratory Langerhans cells, skin migratory classical dermal DCs, CD 103+ dermal DCs, and tissue-resident DCs. The relative role of each of these subsets in inducing T regs has been until now unclear. Using a novel approach that consists of directing antigens to different subsets of DCs in vivo using monoclonal antibodies against surface receptors, we have found strong evidence that not all DCs have the ability to induce regulatory T cells, but instead skin migratory DCs excel in this function. This observation leads to my hypothesis that these subsets of skin migratory DCs are intrinsically programmed by a set of transcriptional factors to induce this type of response. Additionally, local environmental/dietary factors have been described as playing a role in the generation of T regs. For instance, the vitamin A active compound retinoic acid, working in conjunction with TGF- is known to have a positive impact in the induction of T regs in the intestinal tract. Similarly, there is ample evidence in vitro suggesting that vitamin D acts on DCs and/or T cells for the generation of a tolerogenic phenotype. Further, microbiota have recently been shown to play an important role in modulating skin immune responses. The contribution of the proposed research is expected to be: 1) the identification of DC-intrinsic signaling pathways that program subsets of skin migratory DC to the induction of T regs; 2) the determination of the role of vitamins and microbiota, acting on DCs and/or T cells in vivo, to generate T regs; and 3) the evaluation of the suppressive activity of induced T regs in a mouse model of atopic dermatitis. I am prepared to undertake the proposed research since I have all the necessary tools for studying DC functions in vivo, as well as ample experience with DC subsets. The data and skills acquired during the K99 phase of this award have laid a strong foundation for a successful ROO phase. The excellent scientific environment at Stanford University and its commitment to junior faculty are ideal for my transition to independence. This project is of particular relevance because in most skin inflammatory diseases the number of T regs is altered, qualitatively and/or quantitatively, suggesting their role in the pathophysiology of the illness. A detailed comprehension of the mechanisms of DC-mediated T reg induction will help to understand the events that lead to the appearance of skin diseases. Also, this knowledge is likely to be beneficial for the development of new therapeutic targets to increase T reg, which in turn will lead to improved treatment of inflammatory skin diseases and their complications.
Dendritic cells (DCs) are critically important cells of the immune system, which have the capacity to increase the numbers of regulatory T cells (T regs). T regs are specialized immune cells with the ability to stop detrimental skin inflammatory responses, such as atopic dermatitis, psoriasis, contact dermatitis, and pemphigus vulgaris. In this proposal, we will understand the mechanisms that govern skin DC-mediated generation of high numbers of T regs, with the eventual goal of manipulating these responses in vivo for therapeutic purposes.
