IFR 128 BioSciences Gerland - Lyon Sud
U851 INSERM - UCBL
|Team: Pathogen - immune cell interaction: cellular and functional plasticity|
|Team leader: Chantal RABOURDIN-COMBE|
DC-derived MGC: a role for Immune response?
CD46 : a Magnet for Human Pathogens
HLA DR/MHC-II HOECHST/DNA/ nucleus
To replicate and to survive in the organism, a virus has to escape from to the host’s immune system either by subverting it (for acute infections) or by inducing an immunosuppression (for persistent infections). Both mechanisms are involved during Measles virus (MV) infection since the a/b interferon responses are inhibited and MV was the first human virus to be described as being clinically immunosuppressive. Indeed, MV infection gives rise to a paradoxical situation: despite the development of an efficient immune response establishing virus elimination and long-term immunity, around 19 days after MV infection, a transient (1 to 6 weeks) immunosuppression occurs that contributes to secondary infection and mortality especially in developing countries.
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
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)
|Selected results :|
|Team supported by:|