Factors that Contribute to 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 differences in control of the parasite. This difference is linked to MHC haplotype, and protection in BALB/c mice has been attributed to an unusually strong MHC-1 Ld-restricted CD8+ T cell response directed against a peptide derived from the parasite protein GRA6. Our lab has previously shown that the GRA6-Ld specific response is maintained by a proliferative intermediate population that gives rise to large numbers of armed effector T cells throughout chronic infection and shows no signs of functional exhaustion. To further investigate this robust CD8+ T cell response, we characterized the TCR repertoire of GRA6-Ld specific CD8+ T cells after T. gondii infection. We showed that the GRA6-Ld specific T cell response displays a TCR repertoire dominated by the Vβ2 variable chain, limited clonal diversity, a strongly selected CDR3β motif, and a public TCR. Additionally, we showed that another Ld-restricted CD8+ T cell response specific for the F2 peptide from Vaccinia virus also has a preference for Vβ2 and a similarly focused TCR repertoire. The MHC-1 Ld molecule has limited peptide binding compared to conventional MHC molecules such as Kb or Db, which correlates with polymorphisms associated with “elite control” of HIV in humans. To investigate the link between this unusual MHC-1 molecule and the generation of “elite controller” CD8+ T cell responses, we compared the GRA6-Ld specific T cell response to the OVA-Kb specific response restricted to the conventional MHC-1 Kb molecule. GRA6-Ld specific T cells are significantly more protective and resistant to exhaustion in chronic T. gondii infection. Next, we used CRISPR/Cas9 to generate mice with a point mutation (W97R) in the peptide-binding groove of Ld that results in broader peptide binding and investigated the effect of this Ld W97R mutation on another robust Ld-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. We observed an increase in exhaustion marker expression on the IE1-Ld specific CD8+ T cells during chronic MCMV infection. In both systems, T cells restricted to MHC-1 Ld exhibited resistance to exhaustion compared to T cells restricted to an MHC-1 with broader peptide binding, supporting a model in which limited peptide binding my MHC favors protective responses during chronic infection