Cell-mediated immune responses are initiated when a population of pre-immune (or naïve) T cells recognize their cognate ligands in the form of a specific peptide bound to a self major histocompatibility complex molecule (pMHC). This recognition is made possible by highly specific T-cell receptors (TCR) on individual T cell clones specific for a given pMHC complex. The pre-immune T cell repertoire is comprised of populations specific for at least 100,000 different pMHC, each containing multiple clones. It is important to understand the composition of this repertoire because it is the repository of all the host's potential for future cell-mediated immune responses to microbes and tumors, and in some cases its own tissues. . However, the study of pre-immune tumor antigen-specific, or any other pathogen-specific T cell populations within such a diverse T cell repertoire have been extremely difficult due to their low frequency in the body.
A novel soluble pMHC magnetic enrichment technique was therefore developed to analyze naive T cell populations in mice and humans,. Using this procedure, different pMHCII-specific naive CD4+ T cell populations could be identified and enumerated. The size of these populations was found to vary depending on pMHC specificity. Additionally, these differences were directly proportional to the magnitude and TCR gene usage diversity of the primary CD4+ T cell response after immunization with relevant peptide.
Thus, variation in naive T cell frequencies can explain why some peptides give rise to greater T cell responses than others. We explored this issue by enumerating pMHCII-specific CD4+ T cell populations that normally number 20 or 200 cells per mouse. Thymic positive or negative selection was required for optimizing the absolute size pf each population but did not alter the 10-fold ratio between the two populations. Large naïve population size was related to the presence of certain amino acids at T cell receptor contact sites within the peptide. These results suggest that certain MHCII-bound peptides are immunodominant because they contain amino acids with chemical properties that foster binding to many TCRs.