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Research

Our goal is to better understand the biology of human antigen-presenting cells (dendritic cells, macrophages and monocytes) in health and pathology, in order to manipulate the properties of these cells for disease treatment, in particular for cancer and inflammatory diseases. To achieve this, we combine studies of human cells directly isolated from tissues, in vitro models using human cells, and in vivo models in mice.

Recent contributions

Numerous studies in mice have shown that dendritic cells (DC) are a heterogenous population comprising several subsets that differ in their phenotype and ontogeny. We found that human DC, like mouse DC, can be divided into resident DC (which remain in lymphoid organs during their entire lifespan) and migratory DC (which are present in peripheral tissues and migrate to draining lymph nodes) (Segura, J Exp Med, 2012).

Mouse DC subsets also possess distinct functions, leading to the concept of «division of labor» between DC subsets. In particular, the ability to present antigens for the induction of cytotoxic T cell responses (a process termed cross-presentation) has been the focus of intense research. We showed that, while the intracellular mechanisms enabling efficient cross-presentation were conserved between mice and humans, the functional specialization for cross-presentation was different between mice and human DC subsets (Segura, J Exp Med, 2013). We also found that one population of human lymphoid organ DC is specialized for the activation of T follicular helper cells, which are essential for humoral responses (Durand, J Exp Med, 2019).

Monocytes have long been known to be recruited to sites of inflammation and to differentiate in situ into monocyte-derived macrophages and monocyte-derived DC.
We identified and characterized in patients samples the human equivalent of monocyte-derived DC, and found that they are potent inducers of Th17 cells, which are involved in inflammatory responses (Segura, Immunity, 2013). We also showed that these monocyte-derived DC from patients samples are able to cross-present antigens and to activate cytotoxic CD8 T cells (Tang-Huau, Nat Comm, 2018). Finally, we showed that monocyte differentiation into DC versus macrophages is driven by external signals, in particular ligands of the Aryl Hydrocarbon Receptor, a transcription factor sensing metabolites from diet and microbiota (Goudot, Immunity, 2017).

On-going projects

The aims of our current research are:

1- to better characterize the properties of human antigen presenting cells
Despite recent progress, our knowledge of the functional specialization between human antigen-presenting cells remains incomplete. In particular, the properties of human macrophages from different tissues are poorly characterized.

2- to unravel the molecular regulators that drive monocyte differentiation towards DC versus macrophage
How environmental factors impact monocyte fate decision to differentiate towards macrophages versus DC, and what transcription factors orchestrate these developmental pathways remains to be established. In many chronic inflammatory diseases, monocyte-derived cells fuel the inflammation and are responsible for tissue damage. In cancer, monocyte-derived macrophages are major immuno-suppressors in the tumor micro-environment, while monocyte-derived DC have a positive impact by stimulating T cells. By better understanding the molecular regulation of monocyte differentiation, we aim to identify strategies to manipulate this process for improving the efficacy of therapies against cancer and inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.

3- to decipher the role of Aryl Hydrocarbon Receptor in antigen-presenting cells
Aryl Hydrocarbon Receptor is involved in lymphoid cells differentiation and function, but its role in DC, monocytes and macrophages is not fully understood. How diet and microbiota impact these cells via activation of the Aryl Hydrocarbon Receptor is also unclear.


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