Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum

• Published in: Nature immunology Vol. 9; no. 8; pp. 937 - 944
• Main Authors: Joncker, Nathalie T, Schaeffer, Marie, Cheng, Tiffany, Shastri, Nilabh, Gonzalez, Federico, Blanchard, Nicolas, Shastri, Anjali J, Robey, Ellen A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2008; Nature Publishing Group
• Subjects: Animals; Antigen Presentation; Antigens, Protozoan - metabolism; Biomedical and Life Sciences; Biomedicine; Endoplasmic Reticulum - immunology; Histocompatibility Antigens Class I - immunology; Immunology; Infectious Diseases; Leucyl Aminopeptidase - deficiency; Leucyl Aminopeptidase - immunology; Leucyl Aminopeptidase - metabolism; Life Sciences; Mice; Parasites; Protected species; Protozoan Proteins - metabolism; Toxoplasma - immunology; Toxoplasma - physiology; Toxoplasma gondii; Toxoplasmosis; Toxoplasmosis - immunology; Vacuoles - immunology
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.1629

The Toxoplasma gondii peptides recognized by protective CD8 + T cells remain uncharacterized. Shastri and colleagues identify an immunodominant T. gondii peptide generated by a mechanism dependent on the endoplasmic reticulum aminopeptidase ERAAP. The parasite Toxoplasma gondii replicates in a specialized intracellular vacuole and causes disease in many species. Protection from toxoplasmosis is mediated by CD8 + T cells, but the T. gondii antigens and host genes required for eliciting protective immunity are poorly defined. Here we identified GRA6, a polymorphic protein secreted in the parasitophorous vacuole, as the source of the immunodominant and protective decapeptide HF10 presented by the H-2L d major histocompatibility complex class I molecule. Presentation of the HF10–H-2L d ligand required proteolysis by ERAAP, the endoplasmic reticulum aminopeptidase associated with antigen processing. Consequently, expansion of protective CD8 + T cell populations was impaired in T. gondii –infected ERAAP-deficient mice, which were more susceptible to toxoplasmosis. Thus, endoplasmic reticulum proteolysis is critical for eliciting protective immunity to a vacuolar parasite.