Lionel POULIN

Dendritic Cells in Infection and Immunity Laboratory (DCIIL)

Our objectives aim at investigating the roles play by human and mouse dendritic cells (DC) subsets in infection and immunity. The laboratory name, DCIIL, has been chosen to really underline that our Institute philosophy, the resolution of major infectious diseases, is inextricably linked to a better understanding of mouse and human DCs diversity and functions.

The dendritic cell system of antigen-presenting cells (APC) controls immunity and tolerance. Indeed, these cells are able to integrate information from the environment to instruct the immune system to allow the adequate response, e.g. in case of infection with a pathogen. Dendritic cells encompass different members, in steady-state and in inflammatory conditions (see Figure 1). This group of cells is heterogeneous in terms of cell-surface markers, function, and anatomic location. There are multiple DC subsets in both mouse and human, however a lot of mouse DC subsets are still waiting for a human equivalent. In the mouse, these subsets have been established taking into account not only a set of markers to define them, but also their localization (e.g., lymphoid or non-lymphoid tissues), and the precursors and transcription factors required for their development (see Figure 1).


Figure 1: Mouse dendritic cells heterogeneity (adapted from Heath and Carbone, Nature Immunology, 2009). In steady-state, non-lymphoid tissues, like the lung or the skin, contain DCs able to migrate to the draining lymph nodes to instruct the immune system (Migratory). The two main migratory subsets, CD11b+ and CD103+ DCs, share similarities with DCs present in lymphoid tissues (Spleen) and named respectively CD4+ and CD8+ DCs. In inflammatory conditions, caused for example by an invading pathogen in the lung, monocyte-derived DCs are recruited to the invaded site and also participate, with the steady-state DCs, to the immune response.

Figure 2: Human dendritic cells heterogeneity. On the left, human gut lamina propria contains some specific subsets of DCs (defined by the co-expression of specific markers). On the right, these cells are able to migrate to the mesenteric lymph nodes to instruct the immune system (Poulin et al., submitted).


Our past achievements contributed to a better understanding of mouse and human DCs. Notably, we have discovered that mouse skin contains a new subset of DC (see Figure 1: CD103+) (Poulin et al., JEM, 2007), and further characterized its specific function, generation of cytotoxic CD8+ T cells, which are able to remove some cancer and virally-infected cells, by a process called crosspresentation (Henri et al., JEM, 2010). We have shown recently that a similar family of cell exists also in human (see below) (Poulin et al., JEM, 2010; Poulin et al., submitted). In collaboration with the group of Bernard Malissen, we have contributed to show that a new marker can be used in mouse, and in human, to identify and study very precisely the monocyte-derived DCs (see Figure 1: Mono-DC) (Tamoutounour, et al., submitted). In mouse, DC subsets are in a mature age where the better delimitation of the different families of cells allow studying their specific functions, e.g. during infectious conditions.


On the contrary, in human, DC subsets are still in its infancy. In fact, the lack of tools and the restricted access to samples have hampered the level of knowledge in human DC biology. We have characterized recently the human equivalent of mouse CD8+ DC (see Figure 1). This has been achieved by developing new tools for human dendritic cells studies (Poulin et al., JEM, 2010; and for a comment on this paper see: Ueno et al., Nat Biotechnol., 2010 and Gallois et al., Nat Med., 2010). In fact, we have developed an assay to generate these human cells in vitro (cord blood- and bone marrow-derived DC) and in vivo (humanized mice); these tools allow us to modify these cells to study specific genes implicated in their development and functions, as transcription factors involved in their development (e.g. by lentivirus-mediated shRNA silencing) (Poulin et al., submitted). To study these cells different approaches will be envisaged, the best approach will be chosen depending of the aim of the project. Our Institute benefited from the knowhow of different platforms covering from imaging to gene expression techniques.

In sum, as dendritic cells are central in immune response development, we aim to study these cells in specific infectious models present in the Institute (CIIL), by taking into account their diversity. We will need to define first human DC subsets and subsequently their involvement during infection and immunity. Indeed, we will study the biology of the complete human DC family to obtain a complete picture before investigating their involvement, as in mouse, in host-pathogen interactions. Our research interests will be focused on the whole DC family by developing and integrating new mouse concepts in human DC biology. A better characterization of the whole DC network will allow studying and exploiting their specificities to get rid off viral and bacterial infections.

 

References

  1. Poulin LF, Salio M, Griessinger E, et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207(6):1261-1271.
  2. Henri S, Guilliams M, Poulin LF, et al. Disentangling the complexity of the skin dendritic cell network. Immunol Cell Biol. 2010;88(4):366-375.
  3. Poulin LF*, Henri S*, Tamoutounour S, et al. CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J Exp Med. 2010;207(1):189-206 (* equally contributed).
  4. Poulin LF, Henri S, de Bovis B, Devilard E, Kissenpfennig A, Malissen B. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J Exp Med. 2007;204(13):3119-3131.
  5. Henri S, Franz Poulin L, Malissen B. [The skin dermis host a new population of dendritic cells]. Med Sci (Paris). 2008;24(4):346-347.
  6. Gallois A, Bhardwaj N. A needle in the ‘cancer vaccine’ haystack. Nat Med. 2010;16(8):854-856.
  7. Ueno H, Palucka AK, Banchereau J. The expanding family of dendritic cell subsets. Nat Biotechnol. 2010;28(8):813-815.

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