HUMAN CYTOTOXIC T-LYMPHOCYTE REPERTOIRE TO INFLUENZA-A VIRUSES

The murine CD8(+) cytotoxic-T-lymphocyte (CTL) repertoire appears to b e quite limited in response to influenza A viruses. The CTL responses to influenza A virus in humans were examined to determine if the CTL r epertoire is also very limited. Bulk cultures revealed that a number o f virus proteins were recognized in CTL assays, CTL lines were isolate d from three donors for detailed study and found to be specific for ep itopes on numerous influenza A viral proteins. Eight distinct CD8(+) C TL lines were isolated from donor 1. The proteins recognized by these cell lines included the nucleoprotein (NP), matrix protein (M1), nonst ructural protein 1 (NS1), polymerases (PB1 and PB2), and hemagglutinin (HA). Two CD4(+) cell lines, one specific for neuraminidase (NA) and the other specific for MP, were also characterized. These CTL results were confirmed by precursor frequency analysis of peptide-specific gam ma interferon-producing cells detected by ELISPOT. The epitopes recogn ized by 6 of these 10 cell lines have not been previously described; 8 of the 10 cell lines were cross-reactive to subtype H1N1, H2N2, and H 3N2 viruses, 1 cell line was cross-reactive to subtypes H1N1 and H2N2, and 1 cell line was subtype H1N1 specific. A broad CTL repertoire was detected in the two other donors, and cell lines specific for the NP, WA, HA M1, NS1, and M2 viral proteins were isolated. These findings i ndicate that the human memory CTL response to influenza A virus is bro adly directed to epitopes on a wide variety of proteins, unlike the li mited response observed following infection of mice.