Définition des interactions entre l’immunité innée et adaptative pendant l’infection aiguë par le virus de l’hépatite C (VHC)

The majority of individuals exposed to the hepatitis C virus (HCV) develop a chronic infection.  It is known that a strong and sustained adaptive immune response is associated with the spontaneous clearance of HCV, however the underlying mechanisms are not well defined. The role of natural killer (NK) cells and dendritic cells (DCs) during the spontaneous resolution of HCV remains unknown.  NK cells are the primary effector population of the innate immune response which are able to kill infected cells and secrete various cytokines.  On the other hand, DCs are the first cell type to initiate and regulate adaptive immunity after recognizing infectious pathogens.  NK cells and DCs can also interact reciprocally to further regulate innate and adaptive immunity. Our hypothesis is that NK cell activity during acute HCV will modulate DC function to prime a highly efficient adaptive immune response resulting in viral clearance. The first aim of my project was to establish a correlation between NK cell activity and the outcome of HCV infection.  We observed increased NK cell cytotoxicity, but decreased cytokine secretion during acute HCV in patients with chronic evolution as well as spontaneous resolution, further demonstrating a dissociation between these two NK cell functions.  Our results suggest that NK cells are activated during acute HCV infection regardless of infection outcome. The second aim was to establish a correlation between DC phenotype, function and the outcome of infection.  We observed that plasmacytoid DCs (pDCs) from all HCV-infected patients have a more immature phenotype as compared to negative controls, yet this is more pronounced in spontaneous resolvers.  Furthermore, we observed that during the early acute phase, myeloid DCs (mDCs) from all HCV-infected patients, regardless of outcome, have increased production of cytokines as compared to un-infected controls in response to stimulation.  However, this hyperresponsiveness of mDCs is not sustained with chronic evolution. The third aim was to establish a correlation between the NK/DC cross-talk and infection outcome.  We studied the capacity of NK cells to kill potentially tolerogenic DCs, as well as the capacity of mature DCs to activate NK cells, and we observed no major differences between different stages of HCV infection and un-infected controls.  However, we obtained unprecedented data which suggests that immature DCs have the capacity to inhibit NK cell function. In conclusion, our results demonstrate that NK cells are activated during acute HCV infection regardless of its outcome.  Furthermore, the capacity of NK cells to kill potentially tolerogenic DCs is intact for all groups of patients.  Finally, mDCs are hyperresponsive during acute HCV, but this hyperresponsiveness is not sustained with persistence of viremia.  The loss of mDC hyperresponsiveness does not seem to affect the capacity of DCs to activate NK cells, but might play a role in the capacity of DCs to prime a highly efficient adaptive immune response resulting in viral clearance.

Keyphrases: Hepatitis C virus (HCV), HCV spontaneous resolution, Acute HCV, Innate immunity, NK cells, Dendritic cells (DC), NK/DC cross-talk, DC hyperresponsiveness