title: Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/K(b) Transgenic Mice.
abstract: Hantavirus infections cause severe emerging diseases in humans and are associated with high mortality rates; therefore, they have become a global public health concern. Our previous study showed that the CD8(+) T-cell epitope aa129-aa137 (FVVPILLKA, FA9) of the Hantaan virus (HTNV) nucleoprotein (NP), restricted by human leukocyte antigen (HLA)-A*02, induced specific CD8(+) T-cell responses that controlled HTNV infection in humans. However, the in vivo immunogenicity of peptide FA9 and the effect of FA9-specific CD8(+) T-cell immunity remain unclear. Here, based on a detailed structural analysis of the peptide FA9/HLA-A*0201 complex and functional investigations using HLA-A2.1/K(b) transgenic (Tg) mice, we found that the overall structure of the peptide FA9/HLA-A*0201 complex displayed a typical MHC class I fold with Val2 and Ala9 as primary anchor residues and Val3 and Leu7 as secondary anchor residues that allow peptide FA9 to bind tightly with an HLA-A*0201 molecule. Residues in the middle portion of peptide FA9 extruding out of the binding groove may be the sites that allow for recognition by T-cell receptors. Immunization with peptide FA9 in HLA-A2.1/K(b) Tg mice induced FA9-specific cytotoxic T-cell responses characterized by the induction of high expression levels of interferon-γ, tumor necrosis factor-α, granzyme B, and CD107a. In an HTNV challenge trial, significant reductions in the levels of both the antigens and the HTNV RNA loads were observed in the liver, spleen, and kidneys of Tg mice pre-vaccinated with peptide FA9. Thus, our findings highlight the ability of HTNV epitope-specific CD8(+) T-cell immunity to control HTNV and support the possibility that the HTNV-NP FA9 peptide, naturally processed in vivo in an HLA-A*02-restriction manner, may be a good candidate for the development HTNV peptide vaccines.
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Microbiology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Institute of Orthopaedics of Xijing Hospital, The Fourth Military Medical University , Xi'an , China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Yusi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Kang
authors.initials: K
authors.lastname: Tang
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Microbiology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Fanglin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The Fourth Military Medical University , Xi'an , China.
authors.forename: Boquan
authors.initials: B
authors.lastname: Jin
keywords: CD8+ T-cell response; HLA-A*02; HLA-A2.1/Kb transgenic mice; Hantaan virus; crystal structure; cytotoxic T-cell epitope