Cutaneous immune responses must be tightly controlled to prevent inflammatory and allergic diseases, i.e., atopic dermatitis, psoriais, 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 novo from CD4+ naive T cells in the periphery by antigen presenting cells, especially dendritic cell (DCs). The DC system is intricate and is comprised of distinct subsets such as, skin migratory Langerhans cells, skin migratory classical dermal DCs and CD103+ dermal DCs, and tissue-resident DCs. The relative role of each of these subsets in inducing T regs has been until now indeterminate. Using a novel approach that consists of directing antigens to different subsets of DCs in vivo using monoclonal antibodies against surfac receptors, we have found strong evidence that not all DCs have the ability to induce regulatory T cells, but instead skin migratory DC excel in this function. This observation leads to my hypothesis that these subsets of skin migratory DC are intrinsically programmed by a set of transcriptional factors to induce this type of response. Additionally, local environmental/dietary factors are also described to play 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 track. Similarly, ther is ample evidence in vitro suggesting that Vitamin D acts on DCs and/or T cells for generation of a tolerogenic phenotype. 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, acting on DCs and/or T cells in vivo, for the generation of T regs, and 3) the evaluation of the suppressive activity of induced Tregs in a mouse model of atopic dermatitis. We are prepared to undertake the proposed research since we have all the necessary tools for studying DC functions in vivo, as well as, ample experience with DC subsets. With my mentors, I have planned the aims to achieve a comprehensive training in molecular biology approaches and mouse genetic engineering during the K99 phase of the award. 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 disease. Also, this knowledge is likely to be beneficial to the development new therapeutic targets to increase T reg, which in turn will lead to improved treatment of inflammatory skin diseases and their complications.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Career Transition Award (K99)
Project #
1K99AR062595-01
Application #
8280636
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Cibotti, Ricardo
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$95,593
Indirect Cost
$7,081
Name
Rockefeller University
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Flacher, Vincent; Tripp, Christoph H; Mairhofer, David G et al. (2014) Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross-tolerance. EMBO Mol Med 6:1191-204
Idoyaga, Juliana; Fiorese, Christopher; Zbytnuik, Lori et al. (2013) Specialized role of migratory dendritic cells in peripheral tolerance induction. J Clin Invest 123:844-54