MHC Class I/Peptide Stability: Implications for Immunodominance, In Vitro Proliferation, and Diversity of Responding CTL

Abstract

AbstractInfection of BALB/c mice with Listeria monocytogenes primes CD8+ cytotoxic T cells specific for four different H2-Kd-restricted peptides. In vitro restimulation of L. monocytogenes immune splenocytes with each of these peptides resulted in larger T cell responses to p60 217–225 and mpl 84–92 than to LLO 91–99 and p60 449–457. Direct frequency analyses of immune splenocytes, however, revealed that LLO 91–99 and p60 217–225 elicit dominant T cell responses, while p60 449–457 and mpl 84–92 elicit minor, subdominant responses. Restimulation of immune splenocytes with a range of peptide concentrations revealed that T cells with dominant specificities respond optimally to low peptide concentrations, while T cells specific for subdominant epitopes expand maximally to high peptide concentrations. This disparity correlates with the stability of H2-Kd/epitope complexes: the two dominant epitopes form stable complexes, while the subdominant epitopes form less stable complexes with H2-Kd. Interestingly, T cells specific for LLO 91–99 and p60 217–225 express more complex TCR-Vβ repertoires than p60 449–457- and mpl 84–92-specific T cells. Thus, in our system, dominant T cell responses have relatively diverse TCR repertoires and are specific for peptides that form stable complexes with MHC class I molecules. Determining the precise roles of epitope/MHC class I stability and TCR repertoire in the generation of dominant T cell responses will require further investigation.