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PDBsum entry 3p9m
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Immune system
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PDB id
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3p9m
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References listed in PDB file
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Key reference
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Title
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Affinity thresholds for naive cd8+ ctl activation by peptides and engineered influenza a viruses.
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Authors
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A.E.Denton,
R.Wesselingh,
S.Gras,
C.Guillonneau,
M.R.Olson,
J.D.Mintern,
W.Zeng,
D.C.Jackson,
J.Rossjohn,
P.D.Hodgkin,
P.C.Doherty,
S.J.Turner.
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Ref.
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J Immunol, 2011,
187,
5733-5744.
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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High-avidity interactions between TCRs and peptide + class I MHC (pMHCI)
epitopes drive CTL activation and expansion. Intriguing questions remain
concerning the constraints determining optimal TCR/pMHCI binding. The present
analysis uses the TCR transgenic OT-I model to assess how varying profiles of
TCR/pMHCI avidity influence naive CTL proliferation and the acquisition of
effector function following exposure to the cognate H-2K(b)/OVA(257-264)
(SIINFEKL) epitope and to mutants provided as peptide or in engineered influenza
A viruses. Stimulating naive OT-I CD8(+) T cells in vitro with SIINFEKL induced
full CTL proliferation and differentiation that was largely independent of any
need for costimulation. By contrast, in vitro activation with the low-affinity
EIINFEKL or SIIGFEKL ligands depended on the provision of IL-2 and other
costimulatory signals. Importantly, although they did generate potent endogenous
responses, infection of mice with influenza A viruses expressing these same
OVA(257) variants failed to induce the activation of adoptively transferred
naive OT-I CTLps, an effect that was only partially overcome by priming with a
lipopeptide vaccine. Subsequent structural and biophysical analysis of
H2-K(b)OVA(257), H2-K(b)E1, and H2-K(b)G4 established that these variations
introduce small changes at the pMHCI interface and decrease epitope stability in
ways that would likely impact cell surface presentation and recognition.
Overall, it seems that there is an activation threshold for naive CTLps, that
minimal alterations in peptide sequence can have profound effects, and that the
antigenic requirements for the in vitro and in vivo induction of CTL
proliferation and effector function differ substantially.
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