We could recently show that Dendritic cells in the skin closely interact with Innate Lymphoid cells. This interaction leads to the tissue-specific imprinting of dermal Dendritic cells and an anticipatory functionality to protect against parasite/mite infections. Immune circuits formed by the same cell types have been shown to protect other barrier sites, such as the intestine and the lung, but are controlled by tissue-specifc signaling pathways to protect against infection. However, Dendritic cell signaling can also extend to other tissue-resident immune cells, such as regulatory T cells. Especially in the skin, regulatory T cells share certain signatures with dermal Dendritic cells and Innate Lymphoid cells, suggesting a close interaction. We therefore aim to identify how Dendritic cells, Innate Lymphoid cells and regulatroy T cells interact with each other within the skin and if they are regulated by similar molecular pathways that lead to tissue imprinting. In addition we want to understand what role this skin immune circuit plays in chronic disease, such as the development and progression of skin allergy and cancer, where regulatory T cells respectively play a protective or detrimental role.

Dendritic cells (DC) are professional antigen-presenting cells that have an extraordinary ability to stimulate naïve T cells and initiate a primary immune response. DC develop from hematopoietic progenitors in the bone marrow under the control of FLT3L and can be divided into two main lineages: Type 1 DC (DC1), which develop under the control of BATF3 and IRF8, and Type 2 DC (DC2), which require IRF4 for their development. These lineages perform different functions and are enriched in different regions of tissues and lymph nodes. DC1 perform cross-presentation of tumor and viral antigens via MHC class I and start CD8 T cell mediated cytotoxic immune responses. DC2 perform CD4 T helper cell responses, which can range from anti-bacterial and anti-fungal immunity to allergic and humoral responses. While DC1 represent a largely homogeneous population, different DC2 subsets have been reported in different tissues and during immunization with different antigens. We aim to identify the molecular pathways that lead to the differentiation of tissues-specific DC2 populations and determine the unique functionality of these populations. Correlating the development of these populations with enhanced protection or worsening disease progression, will allow us to develop targeted therapeutic approaches to harness the subset-specific functionalities in health and disease.