A Previously Unrecognized H-2D^b-Restricted Peptide Prominent in the Primary Influenza A Virus-Specific CD8⁺T-Cell Response Is Much Less Apparent following Secondary Challenge

Abstract

؉ -T-cell immunodominance heirarchies defined largely by cytotoxic T-lymphocyte assays may need to be revised.

Frequency, Specificity, and Sites of Expansion of CD8+ T Cells during Primary Pulmonary Influenza Virus Infection

“…The frequency of IFN-␥-secreting T cells to each of the defined epitopes was always Ͻ5% at this time, with Ͻ10% of BAL CD8 ϩ T cells in aggregate identified as virus-specific by this criterion. As previously reported in other influenza virus infection models (3)(4)(5), over the next 2-5 days the frequency (percentage) of epitope-specific, IFN-␥-producing CD8 ϩ T cells increased significantly and reached a maximum level by days 9 -10 of infection, with subsequent contraction of the response during the following week (Fig. 1A).…”

“…Furthermore, because influenza virus is a respiratory tract pathogen, much of our current knowledge about the specific CD8 ϩ T cell response to influenza virus has come from analyzing the specificity of the pulmonary CD8 ϩ T cell response to intranasal (i.n.) 3 challenge (3)(4)(5). These important studies have detailed the immunodominance hierarchy to several CD8 ϩ T cell epitopes from the HKx31 (H3N2) and PR/8 (H1N1) influenza viruses in H-2 b mice.…”

“…These important studies have detailed the immunodominance hierarchy to several CD8 ϩ T cell epitopes from the HKx31 (H3N2) and PR/8 (H1N1) influenza viruses in H-2 b mice. The most dominant epitopes from these viruses are polymerase A 224 -233 and nucleoprotein (NP) 366 -374 , which, along with other minor epitopes, are targets for the ϳ40% of pulmonary CD8 ϩ T cells that are identifiable as virus-specific during the primary immune response (3)(4)(5).…”

Heterogeneity of Effector Phenotype for Acute Phase and Memory Influenza A Virus-Specific CTL

“…Although CD8 ϩ T cell responses to the nucleoprotein (NP 366 ) and acid polymerase (PA 224 ) peptides bound to H2-D b (28,29) are approximately equivalent in magnitude following primary influenza A virus challenge of C57BL/6J (B6, H2 b ) mice, the D b PA 224 -specific T cells tend to emerge a little earlier and to show evidence of a more potent effector function (29,30). Although both D b NP 366 -and D b PA 224 -specific CTL demonstrate potent cytotoxicity directly ex vivo (23), little is known about the patterns of CTL-specific effector gene transcription within these populations.…”

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

“…infection of C57BL/6J (B6) mice results in CTL responses directed against a range of pMHCI determinants that fall into a characteristic immunodominance hierarchy (18). The immunodominant CTL populations are specific for pMHCI epitopes derived from the viral nucleoprotein (NP 366 ) (19) and acid polymerase (PA 224 ) (20), while 2 of the subdominant responses are directed at peptides from the basic polymerase subunit 1 frameshift 2 protein (PB1-F2 62 ; ref. 21) and nonstructural protein 2 (NS2 114 ; ref.…”