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PDBsum entry 4gg8
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Immune system
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PDB id
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4gg8
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References listed in PDB file
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Key reference
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Title
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Biased t cell receptor usage directed against human leukocyte antigen dq8-Restricted gliadin peptides is associated with celiac disease.
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Authors
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S.E.Broughton,
J.Petersen,
A.Theodossis,
S.W.Scally,
K.L.Loh,
A.Thompson,
J.Van bergen,
Y.Kooy-Winkelaar,
K.N.Henderson,
T.Beddoe,
J.A.Tye-Din,
S.I.Mannering,
A.W.Purcell,
J.Mccluskey,
R.P.Anderson,
F.Koning,
H.H.Reid,
J.Rossjohn.
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Ref.
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Immunity, 2012,
37,
611-621.
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PubMed id
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Abstract
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Celiac disease is a human leukocyte antigen (HLA)-DQ2- and/or DQ8-associated
T cell-mediated disorder that is induced by dietary gluten. Although it is
established how gluten peptides bind HLA-DQ8 and HLA-DQ2, it is unclear how
such peptide-HLA complexes are engaged by the T cell receptor (TCR), a
recognition event that triggers disease pathology. We show that biased TCR
usage (TRBV9(∗)01) underpins the recognition of HLA-DQ8-α-I-gliadin. The
structure of a prototypical TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin complex shows
that the TCR docks centrally above HLA-DQ8-α-I-gliadin, in which all
complementarity-determining region-β (CDRβ) loops interact with the gliadin
peptide. Mutagenesis at the TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin interface
provides an energetic basis for the Vβ bias. Moreover, CDR3 diversity accounts
for TRBV9(∗)01(+) TCRs exhibiting differing reactivities toward the gliadin
epitopes at various deamidation states. Accordingly, biased TCR usage is an
important factor in the pathogenesis of DQ8-mediated celiac disease.
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