Memory and recall CD8⁺ T cell responses to the influenza A viruses

The recent development of tetrameric complexes of MHC class I glycoprotein+peptide (tetramers) enables, for the first time, accurate quantitation of CD8⁺ T cell responses. The characteristics of the cellular immune response following primary, secondary or even tertiary challenge with serologically distinct influenza A viruses can now be understood much more clearly. The prevalence of H-2D^b-restricted CD8⁺ memory T cells specific for the immunodominant NP_366–374 peptide that stains with the D^bNP₃₆₆ tetramer increases from undetectable levels in naı̈ve mice, to frequencies of 0.2–0.5% (of the CD8⁺ set) following i.p. exposure to an H1N1 virus. This is boosted to >10% when these H1N1-immune mice are exposed intranasally to an H3N2 virus. Further respiratory challenge of these H1N1- or H3N2→H1N1-primed mice with a virulent H7N7 virus shows very clearly that the rate of virus clearance is a direct function of the size of the available CD8⁺ memory T cell pool. However, though established CD8⁺ T cell memory always provides a measure of protection against the development of clinical disease, replicative infection is still established in the face of massive numbers of virus-specific CD8⁺ memory T cells. The implications of these findings for immunization against both influenza and other viruses are discussed.