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

Abstract

The human HLA-A2–restricted CD8+ T cell response to influenza A virus (IAV) is largely directed against the matrix protein-derived M158–66 epitope and represents an archetypal example of CD8+ T cell immunodominance. In this study, we examined the CD8+ T cell hierarchy to M158–66 and two subdominant IAV-specific epitopes: NS1122–130 and PA46–55 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 M158–66–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.