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 smey 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.