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PDBsum entry 2zsv
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Immune system
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PDB id
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2zsv
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References listed in PDB file
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Key reference
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Title
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Prevention of cytotoxic t cell escape using a heteroclitic subdominant viral t cell determinant.
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Authors
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N.S.Butler,
A.Theodossis,
A.I.Webb,
R.Nastovska,
S.H.Ramarathinam,
M.A.Dunstone,
J.Rossjohn,
A.W.Purcell,
S.Perlman.
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Ref.
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Plos Pathog, 2008,
4,
e1000186.
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PubMed id
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Abstract
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High affinity antigen-specific T cells play a critical role during protective
immune responses. Epitope enhancement can elicit more potent T cell responses
and can subsequently lead to a stronger memory pool; however, the molecular
basis of such enhancement is unclear. We used the consensus peptide-binding
motif for the Major Histocompatibility Complex molecule H-2K(b) to design a
heteroclitic version of the mouse hepatitis virus-specific subdominant S598
determinant. We demonstrate that a single amino acid substitution at a secondary
anchor residue (Q to Y at position 3) increased the stability of the engineered
determinant in complex with H-2K(b). The structural basis for this enhanced
stability was associated with local alterations in the pMHC conformation as a
result of the Q to Y substitution. Recombinant viruses encoding this engineered
determinant primed CTL responses that also reacted to the wildtype epitope with
significantly higher functional avidity, and protected against selection of
virus mutated at a second CTL determinant and consequent disease progression in
persistently infected mice. Collectively, our findings provide a basis for the
enhanced immunogenicity of an engineered determinant that will serve as a
template for guiding the development of heteroclitic T cell determinants with
applications in prevention of CTL escape in chronic viral infections as well as
in tumor immunity.
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