Our strategy was to use MV to identify molecular and cellular interactions involved in the immune response. In 1990, we characterized CD46 as the cellular receptor for the MV vaccinal strain. CD46 was first identify to bind and inactivate C3b and C4b complement products, then to act as a cellular receptor for several human pathogens: MV, HHV6, Adenovirus, Streptococcus and Neisseria (see figure 1). Moreover, we demonstrated that CD46 is a molecule of co-stimulation in T cells and that CD46/CD3 co-stimulated cells die after few cell cycles through a mechanism we described as abortive proliferation. Moreover, it has been shown by others that CD3/CD46 co-stimulation of human T cells induced their differentiation into type 1 regulatory T cells (Tr1): these cells produce IFNg and IL-10 but neither IL-2 nor IL-4 and inhibit effector T cell activation. Therefore, by inducing Tr1-tolerizing cells, CD46-using pathogens might escape the immune response.
Such observations opened new fields of investigation to better understand the functional plasticity of CD46. Recently, using two hybrid experiments we have identified new proteins that interact with the CD46 intracytoplamic tails (that can either be Cyt-1 or Cyt-2, due to splice). We currently develop experimental strategies to characterize the physiological relevance of the identified CD46 interactors such as confocal microscopy, si-RNA and the use of CD46-Cyt-1 and CD46-Cyt-2 transgenic mice that we generated in the lab.

In addition lymphocyte functions, antigen presenting cell functions have also shown to be impaired by MV. Indeed, we have demonstrated that MV infection of dendritic cell (DC), described as the only cell able to initiate adaptive immune response, not only abolishes their ability to promote naive T cell activation and proliferation, but also induces apoptosis of DC and T cells quite rapidly (3 days). Therefore, we have suggested that the initiation of the efficient adaptive anti-MV response requires cross-presentation by healthy DC: MV infection induces IFN-beta production which induces TRAIL synthesis by healthy DC, a death factor able to kill infected cells and consequently to provide material for cross-presentation.

Besides, MV-Infected lymphoid tissues contain characteristic multinucleated Warthin-Finkeldey cells in inflamed environment. In this context, three conditions that lead to DC-derived giant cells (or syncitia) have been set up in our laboratory: (i) MV-infected DC then triggered through their CD40 antigen and (ii) DC cultured in the presence of M-CSF and RANK-ligand. This condition gives rise to real osteoclasts (OC): the multinucleated giant cells (MGC) which realize bone resorption. DC “transdifferentiation” into OC is strongly enhanced by the addition of synovial fluids taken from patients with rheumatoid arthritis. (iii) Recently, we have focused our work on a new third pathway of DC fusion which may be involved in diseases exhibiting giant cells inside IFN-gamma-enriched granuloma, such as Langerhans Cell Histiocytosis or tuberculosis.

Finally, in order to extend our knowledge on the host-pathogen interaction between, we will investigate in a global approach though a project called I-MAP for Infections Mapping (see I-MAP team)