CTL recognition of a protective immunodominant influenza A virus nucleoprotein epitope utilizes a highly restricted Vbeta but diverse Valpha repertoire: functional and structural implications |
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Authors: | Zhong Weimin Dixit Surjit B Mallis Robert J Arthanari Haribabu Lugovskoy Alexey A Beveridge David L Wagner Gerhard Reinherz Ellis L |
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Institution: | Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. wzhong@cdc.gov |
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Abstract: | 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. |
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Keywords: | CTL cytotoxic T lymphocytes pMHC peptide bound to self-major histocompatibility complex molecules TCR T cell receptor RACE rapid amplification of cDNA ends MFI mean fluorescence intensity PMA phorbol 12-myristate 13-acetate |
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