Group 2: Bone marrow CD4+ T cells: activation, maintenance and interaction with Mesenchymal Stromal Cells (A. Wakkach)

Equipe 1-groupe 2CD4 + T cells are key players in inflammatory reactions and play a fundamental role in chronic inflammatory diseases and in the link between chronic inflammation and bone destruction. However, the mechanisms responsible for their differentiation and function are not fully understood.

Our recent work has identified a population of Th17 memory cells producing high levels of TNFa and inducing osteoclast differentiation in the context of Crohn's disease (Ciucci et al, Gut 2015). These particular Th17 cells colonize the bone marrow where they participate in the recruitment and differentiation of osteoclastic precursors, leading to the bone destruction frequently associated with this pathology. We have also shown that these cells are present in patients with Crohn's disease, in which they also participate in bone destruction. We have also shown that Th17 cells are accumulated in adipose tissue during obesity, which is also an inflammatory disease associated with bone problems (Bertola et al, Diabetes 2012).

We are currently interested in the mechanisms allowing the migration of these lymphocytes and their retention in the bone marrow in specific niches. We are also developing new therapeutic approaches that would eliminate or control these pathogenic memory lymphocytes. Finally, in collaboration with Team 1, we evaluate the role of ion channels in the differentiation of Th17 cells.

Bone marrow mesenchymal stromal cells (MSC) are essential for the maintenance of memory lymphocytes and are able to modulate the activation of T lymphocytes. In order to explore in humans the interaction between T lymphocytes and MSCs, we have developed a differentiation model of human MSCs from induced pluripotent stem cells (iPS cells) that we generate in vitro. Using this model, we have shown that iPS-derived MSCs are able to inhibit T cell activation in vivo and in vitro and to stimulate the emergence of regulatory T cells in vitro and in vivo. Our current projects are studying the mechanisms responsible for the immunosuppressive function of these iPS-MSCs, as well as their niche function for hematopoietic precursors.