Peripheral "CD8 tuning" dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo

In this study, we suggest that CD8 levels on T cells are not static, but can change and, as a result, modulate CD8⁺ T cell responses. We describe three models of CD8 modulation using novel weak-agonist (K1A) and super-agonist (C2A) altered peptide ligands of the HY smcy peptide. First, we used peripheral nonresponsive CD8^low T cells produced after peripheral HY-D^b MHC class I tetramer stimulation of female HY TCR transgenic and wild-type mice. Second, we used genetically lowered CD8 ^int T cells from heterozygote CD8^+/0 mice. Finally, we used pre-existing nonresponsive CD8^low T cells from male HY TCR transgenic mice. In CD8^low and CD8^high mice, presence of a lower level of CD8 greatly decreased the avidity of the peptide-MHC for HY TCR as reflected by avidity (K_D) and dissociation constant (T _1/2) measurements. All three models demonstrated that lowering CD8 levels resulted in the requirement for a higher avidity peptide-MHC interaction with the TCR to respond equivalently to unmanipulated CD8^high T cells of the same specificity. Additionally, direct injections of wild-type HY-D ^b and C2A-D^b tetramers into female HY TCR or female B6 mice induced a high frequency of peripheral nonresponsive CD8^low T cells, yet C2A-D^b was superior in inducing a primed CD8 ⁺CD44⁺ memory population. The ability to dynamically modulate the size and responsiveness of an Ag-specific T cell pool by "CD8 tuning" of the T cell during the early phases of an immune response has important implications for the balance of responsiveness, memory, and tolerance.