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Study antigen presentation to CD8 T cells during chronic toxoplasmosis, with a focus on cerebral tissue (N. Blanchard)

CD8 T cells are key players in protective immunity against T. gondii and Plasmodium. Paradoxically, they can also become pathogenic as is the case during experimental cerebral malaria. Because both T. gondii and Plasmodium dwell within a vacuole segregated from the host cytosol, parasite-derived antigens need to reach beyond the vacuole membrane in order to access the MHC I pathway. This poses major cell biology challenges which are still poorly understood.

Using genetically modified T. gondii and antigen-specific tools (e.g. T cell hybridomas), we have already identified some parameters that control processing of T. gondii antigens in infected cells. Building up on our discovery of a strongly immunogenic protein of T. gondii (GRA6), we demonstrated that the location of the epitope at the C-terminus of the source antigen critically determines processing, immunodominance and protection by GRA6-specific CD8 T cells (Feliu et al, PLoS Path 2013).

The host-T. gondii interface comprises both the vacuole membrane and an IntraVacuolar Network of tubular membranes (IVN) binding to several T. gondii proteins. Yet whether the IVN plays any role in modulating immunity to the parasite was unknown. Using parasite mutants with perturbed GRA6 transport, we showed that membrane binding regulates access of T. gondii Ag to the MHC I pathway. While insertion of the Ag at the vacuole limiting membrane is key for immunogenicity, its association to the IVN limits presentation and curtails GRA6-specific CD8 responses. Our data suggest that membrane deformations of the IVN play a role in immune modulation (Lopez et al, Cell Reports 2015).

Based on these data, we are now addressing 3 specific aims
1- decipher how vacuole membrane deformations modulate host-parasite exchanges and analyze the lipid and protein make-up of the IVN (Julien Santi-Rocca, post-doc)
2- define the modalities of antigen presentation in the brain during chronic toxoplasmosis (Anna Salvioni, PhD student)
3- examine the impact of antigen location on MHC I presentation during liver stage malaria infection using the P. berghei model (Marion Draheim, PhD student)

Mosaic of "rosette"-like vacuoles containing the Toxoplasma gondii parasite in human fibroblast

Mouse fibroblast invaded by T. gondii parasites

Last updated June 28, 2017

Centre de physiopathologie de Toulouse Purpan - CHU Purpan - BP 3028 31024 Toulouse Cedex 3
Inserm University of Toulouse Université Toulouse III - Paul Sabatier