CTL recognition of a protective immunodominant influenza A virus nucleoprotein epitope utilizes a highly restricted Vbeta but diverse Valpha repertoire: functional and structural implications.
To investigate protective immunity conferred by CTL against viral pathogens, we have analyzed CD8(+) T cell responses to the immunodominant nucleoprotein epitope (NP(366-374)) of influenza A virus in B6 mice during primary and secondary infections in vivo. Unlike the highly biased TCR Vbeta repertoire, the associated Valpha repertoire specific for the NP(366-374)/D(b) ligand is quite diverse. Nonetheless, certain public and conserved CDR3alpha clonotypes with distinct molecular signatures were identified. Pairing of public Valpha and Vbeta domains creates an alphabeta TCR heterodimer that binds efficiently to the NP(366-374)/D(b) ligand and stimulates T cell activation. In contrast, private TCRs, each comprising a distinct alpha chain paired with the same public beta chain, interact very differently. Molecular dynamics simulation reveals that the conformation and mobility of the shared Vbeta CDR loops are governed largely by the associated Valpha domains. These results provide insight into molecular principles regarding public versus private TCRs linked to immune surveillance after infection with influenza A virus.
Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. wzhong@cdc.gov
Weimin
W
Zhong
Surjit B
SB
Dixit
Robert J
RJ
Mallis
Haribabu
H
Arthanari
Alexey A
AA
Lugovskoy
David L
DL
Beveridge
Gerhard
G
Wagner
Ellis L
EL
Reinherz
D000818:Animals; D017124:Conserved Sequence; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D009980:Influenza A virus / Q000737:chemistry / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D011487:Protein Conformation; D016601:RNA-Binding Proteins / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology
D016056:Immunodominant Epitopes; D007376:Interleukin-2; D008024:Ligands; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014758:Viral Core Proteins