PMID- 35065967
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20220531
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 298
IP  - 3
DP  - 2022 Mar
TI  - Structural basis of T cell receptor specificity and cross-reactivity of two 
      HLA-DQ2.5-restricted gluten epitopes in celiac disease.
PG  - 101619
LID - S0021-9258(22)00059-X [pii]
LID - 10.1016/j.jbc.2022.101619 [doi]
LID - 101619
AB  - Celiac disease is a T cell-mediated chronic inflammatory condition often 
      characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten 
      epitopes derived from wheat, barley, and rye. Although some T cells exhibit 
      cross-reactivity toward distinct gluten epitopes, the structural basis 
      underpinning such cross-reactivity is unclear. Here, we investigated the T-cell 
      receptor specificity and cross-reactivity of two immunodominant wheat gluten 
      epitopes, DQ2.5-glia-alpha1a (PFPQPELPY) and DQ2.5-glia-omega1 (PFPQPEQPF). We show by 
      surface plasmon resonance that a T-cell receptor alpha variable (TRAV) 
      4(+)-T-cell receptor beta variable (TRBV) 29-1(+) TCR bound to HLA-DQ2.5-glia-alpha1a 
      and HLA-DQ2.5-glia-omega1 with similar affinity, whereas a TRAV4(-) (TRAV9-2(+)) TCR 
      recognized HLA-DQ2.5-glia-omega1 only. We further determined the crystal structures 
      of the TRAV4(+)-TRBV29-1(+) TCR bound to HLA-DQ2.5-glia-alpha1a and 
      HLA-DQ2.5-glia-omega1, as well as the structure of an epitope-specific 
      TRAV9-2(+)-TRBV7-3(+) TCR-HLA-DQ2.5-glia-omega1 complex. We found that position 7 
      (p7) of the DQ2.5-glia-alpha1a and DQ2.5-glia-omega1 epitopes made very limited contacts 
      with the TRAV4(+) TCR, thereby explaining the TCR cross-reactivity across these 
      two epitopes. In contrast, within the TRAV9-2(+) TCR-HLA-DQ2.5-glia-omega1 ternary 
      complex, the p7-Gln was situated in an electrostatic pocket formed by the 
      hypervariable CDR3beta loop of the TCR and Arg70beta from HLA-DQ2.5, a polar network 
      which would not be supported by the p7-Leu residue of DQ2.5-glia-alpha1a. In 
      conclusion, we provide additional insights into the molecular determinants of TCR 
      specificity and cross-reactivity to two closely-related epitopes in celiac 
      disease.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Ciacchi, Laura
AU  - Ciacchi L
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 
      Australia.
FAU - Farenc, Carine
AU  - Farenc C
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 
      Australia.
FAU - Dahal-Koirala, Shiva
AU  - Dahal-Koirala S
AD  - Department of Immunology, University of Oslo and Oslo University 
      Hospital-Rikshospitalet, Oslo, Norway; K. G. Jebsen Centre for Coeliac Disease 
      Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
FAU - Petersen, Jan
AU  - Petersen J
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 
      Australia.
FAU - Sollid, Ludvig M
AU  - Sollid LM
AD  - Department of Immunology, University of Oslo and Oslo University 
      Hospital-Rikshospitalet, Oslo, Norway; K. G. Jebsen Centre for Coeliac Disease 
      Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
FAU - Reid, Hugh H
AU  - Reid HH
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 
      Australia.
FAU - Rossjohn, Jamie
AU  - Rossjohn J
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 
      Australia; Institute of Infection and Immunity, School of Medicine, Cardiff 
      University, Cardiff, United Kingdom. Electronic address: 
      Jamie.rossjohn@monash.edu.
LA  - eng
PT  - Journal Article
DEP - 20220121
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Complementarity Determining Regions)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (Immunodominant Epitopes)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 8002-80-0 (Glutens)
SB  - IM
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - *Celiac Disease/immunology
MH  - Complementarity Determining Regions/metabolism
MH  - Cross Reactions/immunology
MH  - Epitopes, T-Lymphocyte/chemistry/immunology
MH  - *Glutens/immunology
MH  - *HLA-DQ Antigens/chemistry/immunology
MH  - Humans
MH  - Immunodominant Epitopes/metabolism
MH  - Receptors, Antigen, T-Cell/chemistry/immunology
MH  - T-Cell Antigen Receptor Specificity/immunology
PMC - PMC8857473
OTO - NOTNLM
OT  - T cell receptor
OT  - X-ray crystallography
OT  - autoimmunity
OT  - celiac disease
OT  - human leukocyte antigen
COIS- Conflict of interest The authors declare that they have no conflict of interest 
      with the contents of this article.
EDAT- 2022/01/24 06:00
MHDA- 2022/04/16 06:00
PMCR- 2022/01/21
CRDT- 2022/01/23 20:29
PHST- 2021/10/15 00:00 [received]
PHST- 2022/01/15 00:00 [revised]
PHST- 2022/01/18 00:00 [accepted]
PHST- 2022/01/24 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2022/01/23 20:29 [entrez]
PHST- 2022/01/21 00:00 [pmc-release]
AID - S0021-9258(22)00059-X [pii]
AID - 101619 [pii]
AID - 10.1016/j.jbc.2022.101619 [doi]
PST - ppublish
SO  - J Biol Chem. 2022 Mar;298(3):101619. doi: 10.1016/j.jbc.2022.101619. Epub 2022 
      Jan 21.