T cell immunodominance is dictated by the positively selecting self-peptide

Naive T cell precursor frequency determines the magnitude of immunodominance. While a broad T cell repertoire requires diverse positively selecting self-peptides, how a single positively selecting ligand influences naive T cell precursor frequency remains undefined. We generated a transgenic mouse expressing a naturally occurring self-peptide, gp250, that positively selects an MCC-specific TCR, AND, as the only MHC class II I-E_k ligand to study the MCC highly organized immunodominance hierarchy. The single gp250/I-E_k ligand greatly enhanced MCC-tetramer⁺ CD4⁺ T cells, and skewed MCC-tetramer⁺ population toward V11α⁺Vβ3⁺, a major TCR pair in MCC-specific immunodominance. The gp250-selected V11α⁺Vβ3⁺ CD4⁺ T cells had a significantly increased frequency of conserved MCC-preferred CDR3 features. Our studies establish a direct and causal relationship between a selecting self-peptide and the specificity of the selected TCRs. Thus, an immunodominant T cell response can be due to a dominant positively selecting self-peptide.