Terminal deoxynucleotidyl transferase establishes and broadens antiviral CD8⁺ T cell immunodominance hierarchies

The action of TdT on mouse TCR genes accounts for ∼90% of T cell repertoire diversity. We report that in TdT^-/- mice, total T _CD8⁺ responses to influenza and vaccinia viruses are reduced by ∼30% relative to wild-type mice. We find that T _CD8⁺ responses to three subdominant influenza virus determinants are reduced to background values in TdT^-/- mice while responses to three immunodominant determinants undergo a major reshuffling. A similar reshuffling occurs in T_CD8⁺ responses to immunodominant vaccinia virus determinants, and is clearly based on broad differences in TCR family usage and CDR3 length between wild-type and TdT ^-/- mice. These findings demonstrate that TdT plays a critical role in the magnitude and breadth of anti-viral T_CD8⁺ responses toward individual determinants and suggests that germline TCR repertoire bias toward the most dominant determinants is a major factor in establishing immunodominance hierarchies.