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Innate Lymphoid cell/Dendritic cell interactions in the skin
We could recently show that Dendritic cells in the skin closely interact with Innate Lymphoid cells. Under homeostatic conditions this interaction leads to the local differentiation of CD11b-low dermal Dendritic cells and an anticipatory functionality to protect against parasite/mite infections. How this interaction is maintained in the steady state and perturbed during skin inflammation and infection are current questions we are trying to address by assessing Innate Lymphoid cell/Dendritic cell interaction within the epidermis, dermis and subcutis using 30-color flow cytometry, single-cell sequencing and multiplex imaging.
DC Plasticity and Tissue Specificity
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.
DC Suppression through the Tumor Microenvironment
Different escape strategies have been characterized in aggressive tumors that prevent efficient immune recognition or tumor killing. Some of these mechanisms require cell-cell interaction, while others are mediated through soluble factors. Soluble factors within the tumor microenvironment (TME) can originate from different sources, such as tumor cells, recruited immune cells and the surrounding stroma. In most settings the TME has a suppressive activity further impairing anti-tumor immunity. While the TME can affect monocyte and macrophage behavior and differentiation, less is known about its effect on Dendritic cells (DC). DC are critical for priming naive T cells against tumor antigens and can present antigens from tumor cells or from the TME. We aim to address if the TME influences the ability of DC on how they present antigen and determine the molecular processes of DC reprogramming or suppression. Being able to inhibit the suppressive effects of the TME and rescue DC functionality might be an attractive target to increase effective anti-tumor immune responses, as strong DC responses in tumor settings have been associated with improved survival.
Dendritic Cell immuno-metabolomics
The field of immunometabolism has advanced our understanding of how intracellular metabolic pathways alter immune cells function. Immune cells can undergo metabolic reprogramming to support different types of cellular functions and activities. Dendritic cells, as key players in immune surveillance, are responsible for detecting and presenting pathogen and tumor antigens to T cells. However, in the context of infection and cancer, changes within the microenvironment can affect the cellular metabolism of immune cells. While currently understudied, the metabolic profile of Dendritic cells also undergoes significant alterations, which might impair their function and promoting persistent infection or tumor immune evasion. We aim to develop new techniques to profile the metabolic reprogramming of DCs in infection and cancer and identify how metabolic shifts might contribute to immune suppression and tumor progression. These findings may uncover potential therapeutic strategies to modulate DC metabolism to enhance pro-inflammatory immunity in the context of infection and cancer.
Thank you for your support
We thank all patients and healthy volunteers involved in our studies for their participation.
We appreciate the financial support from the following public and private funding agencies:
Deutsche Forschungsgemeinschaft (DFG)
Unimedizin Mainz
Boehriger Ingelheim Stiftung
von Behring Röntgen Stiftung
SANOFI/Genzyme
P.E. Kempkes Stiftung
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