The CMV-Specific CD8⁺ T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities

Evolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricted by its peptide epitope and the presenting major histocompatibility complex (pMHC). It remains unclear how many TCR sequences are recruited into an antigen-specific T cell response, both within and across different organisms, and which factors shape both of these distributions. Infection of mice with ovalbumin-expressing cytomegalovirus (IE2-OVA-mCMV) represents a well-studied model system to investigate T cell responses given their size and longevity. Here we investigated > 180,000 H2k^b/SIINFEKL-recognizing TCR CDR3α or CDR3β sequences from 25 individual mice spanning seven different time points during acute infection and memory inflation. In-depth repertoire analysis revealed that from a pool of highly diverse, but overall limited sequences, T cell responses were dominated by public clonotypes, partly with unexpectedly extreme degrees of sharedness between individual mice ("supra-public clonotypes"). Public clonotypes were found exclusively in a fraction of TCRs with a high generation probability. Generation probability and degree of sharedness select for highly functional TCRs, possibly mediated through elevating intraindividual precursor frequencies of clonotypes.