Precursor frequency and competition dictate the HLA-A2-restricted CD8 + T cell responses to influenza A infection and vaccination in HLA-A2.1 transgenic mice

The human HLA-A2-restricted CD8 ⁺ T cell response to influenza A virus (IAV) is largely directed against the matrix proteinderived M1 _58-66 epitope and represents an archetypal example of CD8 ⁺ T cell immunodominance. In this study, we examined the CD8 ⁺ T cell hierarchy to M1 _58-66 and two subdominant IAV-specific epitopes: NS1 ^122-130 and PA _46-55 in HLA-A2 ⁺ human subjects and HLA-A2.1 transgenic (HHD) mice. Using epitope-based lipopeptides, we show that the CD8 ⁺ T cell hierarchy induced by IAV infection could also be induced by lipopeptide vaccination in a context outside of viral infection when the Ag load is equalized. In the HHD HLA-A2.1 mouse model, we show that the naive T cell precursor frequencies, and competition at the Ag presentation level, can predict the IAV-specific CD8 ⁺ T cell hierarchy. Immunization of mice with subdominant epitopes alone was unable to overcome the dominance of the M1 _58-66-specific response in the face of IAV challenge; however, a multiepitope vaccination strategy was most effective at generating a broad and multispecific response to infection.