Differential Recognition of Influenza A Viruses by M1(58-66) Epitope-Specific CD8(+) T Cells Is Determined by Extraepitopic Amino Acid Residues

作者：van de Sandt Carolien E; Kreijtz Joost H C M; Geelhoed Mieras Martina M; Nieuwkoop Nella J; Spronken Monique I; van de Vijver David A M C; Fouchier Ron A M; Osterhaus Albert D M E; Rimmelzwaan Guus F

来源：Journal of Virology, 2016, 90(2): 1009-1022.

DOI：10.1128/JVI.02439-15

<jats:title>ABSTRACT</jats:title><jats:p>Natural influenza A virus infections elicit both virus-specific antibody and CD4<jats:sup>+</jats:sup>and CD8<jats:sup>+</jats:sup>T cell responses. Influenza A virus-specific CD8<jats:sup>+</jats:sup>cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201-restricted matrix protein 1 (M1<jats:sub>58–66</jats:sub>) epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extraepitopic amino acid substitutions. Activation of specific T cells was used as an indication of antigen presentation. Here, we show that the M1<jats:sub>58–66</jats:sub>epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrate that naturally occurring variations at extraepitopic amino acid residues affect CD8<jats:sup>+</jats:sup>T cell recognition of the M1<jats:sub>58–66</jats:sub>epitope. These data indicate that human influenza A viruses can impair recognition by M1<jats:sub>58–66</jats:sub>-specific CTLs while retaining the conserved amino acid sequence of the epitope, which may represent a yet-unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses.</jats:p><jats:p><jats:bold>IMPORTANCE</jats:bold>Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8<jats:sup>+</jats:sup>cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes, mutations occur that allow influenza A viruses to evade recognition by CTLs. However, the immunodominant HLA-A*0201-restricted M1<jats:sub>58–66</jats:sub>epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M1<jats:sub>58–66</jats:sub>epitope that influence the recognition of the epitope. These results provide novel insights into the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses.</jats:p>

• 出版日期2016-1