An Unusual MHC Molecule Generates Protective CD8+ T Cell Responses to Chronic Infection

The CD8+ T cell response to the intracellular parasite Toxoplasma gondii varies dramatically between mouse strains, resulting in stark differences in control of the parasite. Protection in BALB/c mice can be attributed to an unusually strong and protective MHC-1 L^d-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 L^d molecule has limited peptide binding compared to conventional MHC molecules such as K^b or D^b, which correlates with polymorphisms associated with "elite control" of HIV in humans. To investigate the link between the unusual MHC-1 molecule L^d and the generation of "elite controller" CD8+ T cell responses, we compared the GRA6-L^d specific T cell response to the well-studied OVA-K^b specific response, and demonstrated that GRA6-L^d specific T cells are significantly more protective and resistant to exhaustion in chronic T. gondii infection. To further investigate the connection between limited peptide presentation and robust T cell responses, we used CRISPR/Cas9 to generate mice with a point mutation (W97R) in the peptide-binding groove of L^d that results in broader peptide binding. We investigated the effect of this L^d W97R mutation on another robust L^d-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. This mutation leads to an increase in exhaustion markers in the IE1-L^d specific CD8+ T cell response. Our results indicate that limited peptide binding by MHC-1 L^d correlates with the development of robust and protective CD8+ T cell responses that may avoid exhaustion during chronic infection.