Incomplete CD8 T lymphocyte differentiation as a mechanism for subdominant cytotoxic T lymphocyte responses to a viral antigen

CD8 cytotoxic T lymphocytes (CTLs) recognize antigen in the context of major histocompatibility complex (MHC) class I molecules. Class I epitopes have been classified as dominant or subdominant depending on the magnitude of the CTL response to the epitope. In this report, we have examined the in vitro memory CTL response of H-2(d) haplotype murine CD8 T lymphocytes specific for a dominant and subdominant epitope of influenza hemagglutinin using activation marker expression and staining with soluble tetrameric MHC- peptide complexes. Immune CD8 T lymphocytes specific for the dominant HA204-210 epitope give rise to CTL effectors that display activation markers, stain with the HA204 tetramer, and exhibit effector functions (i.e., cytolytic activity and cytokine synthesis). In contrast, stimulation of memory CD8 T lymphocytes directed to the subdominant HA210-219 epitope results in the generation of a large population of activated CD8 T cells that exhibit weak cytolytic activity and fail to stain with the HA210 tetramer. After additional rounds of restimulation with antigen, the HA210- 219-specific subdominant CD8 T lymphocytes give rise to daughter cells that acquire antigen-specific CTL effector activity and transition from a HA210 tetramer-negative to a tetramer-positive phenotype. These results suggest a novel mechanism to account for weak CD8 CTL responses to subdominant epitopes at the level of CD8 T lymphocyte differentiation into effector CTL. The implications of these findings for CD8 T lymphocyte activation are discussed.