Abstract
HLA class I presentation of pathogen-derived peptide ligands is essential for CD8+ T-cell recognition of Toxoplasma gondii infected cells. Currently, little data exist pertaining to peptides that are presented after T. gondii infection. Herein we purify HLA-A*02:01 complexes from T. gondii infected cells and characterize the peptide ligands using LCMS. We identify 195 T. gondii encoded ligands originating from both secreted and cytoplasmic proteins. Surprisingly, T. gondii ligands are significantly longer than uninfected host ligands, and these longer pathogen-derived peptides maintain a canonical N-terminal binding core yet exhibit a C-terminal extension of 1-30 amino acids. Structural analysis demonstrates that binding of extended peptides opens the HLA class I F' pocket, allowing the C-terminal extension to protrude through one end of the binding groove. In summary, we demonstrate that unrealized structural flexibility makes MHC class I receptive to parasite-derived ligands that exhibit unique C-terminal peptide extensions.
Highlights
CD8 T-cells mediate immunity to Toxoplasma gondii infection (Khan et al, 1988; Suzuki and Remington, 1988) through recognition of peptide antigens presented by the MHC class I (MHC I) molecules of infected cells (Brown and McLeod, 1990; Deckert-Schluter et al, 1994)
T. gondii ligands are significantly longer than uninfected host ligands, and these longer pathogenderived peptides maintain a canonical N-terminal binding core yet exhibit a C-terminal extension of 1–30 amino acids
The production of 12 mg HLA-A*02:01 from infected cells was sufficient for a comprehensive analysis of T. gondii peptide ligands
Summary
CD8 T-cells mediate immunity to Toxoplasma gondii infection (Khan et al, 1988; Suzuki and Remington, 1988) through recognition of peptide antigens presented by the MHC class I (MHC I) molecules of infected cells (Brown and McLeod, 1990; Deckert-Schluter et al, 1994). The majority of peptide ligands identified to date are derived from parasite surface proteins, proteins localized to dense granules, or the rhoptry proteins which are specialized secretory granules whose contents are released either into the host cell cytoplasm or the parasitophorous vacuole (Blanchard et al, 2008; Cardona et al, 2015; Cong et al, 2011). These secreted proteins are thought to be optimal candidates for MHC I presentation because they have the best access to conventional antigen processing and presentation machinery in the host cell.
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