Human memory CTL response specific for influenza A virus is broad and multispecific

Class I restricted cytotoxic T-lymphocyte (CTL) responses are thought to be focused against few immunodominant epitopes. In humans, an often quoted example of such narrow focus is the influenza A (FLU) matrix 58-66 specific memory CTL activity, detectable in HLA-AZ individuals as a result of natural infection. Herein, we analyzed the repertoire of memory, FLU-specific CTLs in A2 and A11 positive individuals. Eighteen A2.1 binding peptides, derived from the FLU-Puerto Rico/8/34 (PR8) isolate, elicited CTL activity in A2.1/Kb transgenic mice upon direct immunization. These peptides were also tested for their capacity to recall memory CTL responses From peripheral blood mononuclear cells (PBMC) of human A2.1 donors. Besides the known dominant M1.58 peptide, 5 new epitopes (PA.46, PA.225, PB1.413, NA.75 and M1.59) were identified. Similarly, eleven, All-binding, FLU-PR8 peptides, which were immunogenic in HLA-A11/Kb transgenic mice, were assayed fur induction of recall CTL responses using peripheral blood lymphocytes from a cohort of All-positive donors. Fight different peptides (NP.188, NP.342, HA.63 HA.149 HA.450, M1.13, M1.178, and M2.70) induced memory CTL activity. Several of these peptides were found to be highly conserved amongst: different FLU isolates, and also capable of binding multiple A3 and A11 supertype molecules. Finally, 37 HLA-B7 binding peptides were also identified. In conclusion, a previously unappreciated breadth of FLU-specific, memory CTL responses in humans was revealed. The relevance of these findings to the design of multiepitope vaccines is discussed. Human Immunology 61, 438-452 (2000). (C) American Society for Histocompatibility and Immunogenetics, 2000. Published by Elsevier Science Inc.