Many immune cells develop from hematopoietic stem cells within the bone marrow throughout life and can be broadly classified into lymphoid and myeloid lineages. As Dendritic cells only live for several days they are constantly replenished by new cells, which differentiate from bone marrow precursors. A complex hierarchy controls the Dendritic cell development of functionally distinct lineages. The lymphoid lineage through CLP (common lymphoid progenitors) gives rise to pre-pDC and, subsequently, plasmacytoid DC (pDC). On the other hand, the myeloid lineage differentiates into monocyte-DC progenitors (MDP), which further differentiate into common DC progenitors (CDP), Ly6C+ MDP, and common monocyte progenitors (cMoP). CDP then develop into pre-cDC1 and pre-cDC2, which eventually give rise to cDC1 and cDC2, respectively. Ly6C+ MDP differentiate into Pro-DC3 and from there into DC3, while cMoP give rise to monocytes that potentially develop into monocyte-derived DCs (moDCs), which can be identified in certain inflammatory conditions. While all these populations exit the bone marrow to disseminate into tissues, Dendritic cells show a complex heterogeneity when isolated from tissues (such as selective expression of CD103, CD301b, CX3CR1, CD11b, etc.), suggesting local adaptation to the microenvironment. Thanks to highly refined single-cell studies, novel populations, like pDC-like cells, which are believed to originate from pre-pDCs and give rise to cDC2 and RORyt-expressing Dendritic cells keep being discovered. 

We are actively trying to incorporate old and new knowledge into our ever-growing understanding of Dendritic cell heterogeneity and biology and propose to more stringently define our naming conventions for Dendritic cells. We propose to divide Dendritic cells into two primary lineages, myeloid (cDC) and lymphoid (pDC). Then Dendritic cell subsets are defined as cells that have a distinct progenitor and are conserved across tissues, such as pDC, cDC1, cDC2, and DC3. Following this, tissue-specific phenotypes can be identified (such as Dendritic cells expressing CD103, low levels of CD11b, etc.). Lastly, Dendritic cell states can be defined based on their expression of activation, proliferation or co-inhibitory molecules, which are often transitory and highly context dependent. 

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.

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.

Ageing plays an increasingly important role in our understanding of immune responses. We are aiming to understand how dendritic cell biology changes with age, focusing on two major aspects. On the one hand we try to understand how Dendritic cell biology is impacted cell-intrinsically, as it is well established that aged individuals have a skewed developmental program of immune cell progenitors in the bone marrow, leading to a skewed output, a more proinflammatory phenotype and epigenetic changes. These changes could therefore directly impact Dendritic cell biology and their output. 

On the other hand, tissue inflammaging describes a more proinflammatory microenvironment, observed particularly in barrier tissues of aged individuals. This is mainly linked to less effective barrier functions, as epithelial cell turnover is decreased, barriers can become leaky and tonic levels of proinflammatory cytokines are observed. These changes within the local environment are likely also sensed by dendritic cells, resulting in changes in their local tissue adaptation and activation status. To understand and delineate the cell-intrinsic and cell-extrinsic changes affecting Dendritic cell biology in aged individuals therefore requires studying both their development and interaction within the local tissue environment.