MHC class I/peptide stability: Implications for immunodominance, in vitro proliferation, and diversity of responding CTL

Infection of BALB/c mice with Listeria monocytogenes primes CD8⁺ cytotoxic T cells specific for four different H2-Kd-restricted peprides. In vitro restimulatton 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-K(d)/epitope complexes: the two dominant epitopes form stable complexes, while the subdominant epitopes form less stable complexes with H2-K(d). 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.