PMID- 31457096
OWN - NLM
STAT- MEDLINE
DCOM- 20200507
LR  - 20200507
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 5
IP  - 8
DP  - 2019 Aug
TI  - Discriminative T cell recognition of cross-reactive islet-antigens is associated 
      with HLA-DQ8 transdimer-mediated autoimmune diabetes.
PG  - eaaw9336
LID - 10.1126/sciadv.aaw9336 [doi]
LID - eaaw9336
AB  - Human leukocyte antigen (HLA)-DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers 
      exceptionally high risk in autoimmune diabetes. However, little is known about 
      HLA-DQ8 transdimer-restricted CD4 T cell recognition, an event crucial for 
      triggering HLA-DQ8 transdimer-specific anti-islet immunity. Here, we report a 
      high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 
      and HLA-DQ8 transdimer. Despite preservation of putative residues for T cell 
      receptor (TCR) contact, stronger disease-associated responses to cross-reactive, 
      immunodominant islet epitopes are elicited by HLA-DQ8 transdimer. Mutagenesis at 
      the alpha chain of HLA-DQ8 transdimer in complex with the disease-relevant 
      GAD65(250-266) peptide and in silico analysis reveal the DQ alpha52 residue located 
      within the N-terminal edge of the peptide-binding cleft for the enhanced T cell 
      reactivity, altering avidity and biophysical affinity between TCR and HLA-peptide 
      complexes. Accordingly, a structurally promiscuous but nondegenerate 
      TCR-HLA-peptide interface is pivotal for HLA-DQ8 transdimer-mediated autoimmune 
      diabetes.
FAU - Chow, I-Ting
AU  - Chow IT
AUID- ORCID: 0000-0001-7278-8157
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - Gates, Theresa J
AU  - Gates TJ
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - Papadopoulos, George K
AU  - Papadopoulos GK
AUID- ORCID: 0000-0002-6944-6591
AD  - Laboratory of Biophysics, Biochemistry, Bioprocessing and Bioproducts, Faculty of 
      Agricultural Technology, Technological Educational Institute of Epirus, GR47100 
      Arta, Greece.
FAU - Moustakas, Antonis K
AU  - Moustakas AK
AD  - Department of Food Technology, Ionian University, GR28100 Argostoli, Cephallonia, 
      Greece.
FAU - Kolawole, Elizabeth M
AU  - Kolawole EM
AUID- ORCID: 0000-0003-3138-0037
AD  - Department of Pathology, University of Utah School of Medicine, Salt Lake City, 
      UT 84132, USA.
FAU - Notturno, Richard J
AU  - Notturno RJ
AUID- ORCID: 0000-0002-1348-6359
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - McGinty, John W
AU  - McGinty JW
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - Torres-Chinn, Nadia
AU  - Torres-Chinn N
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - James, Eddie A
AU  - James EA
AUID- ORCID: 0000-0002-7217-5729
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - Greenbaum, Carla
AU  - Greenbaum C
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
FAU - Nepom, Gerald T
AU  - Nepom GT
AUID- ORCID: 0000-0002-8063-1464
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
AD  - Department of Immunology, University of Washington, Seattle, WA 98195, USA.
FAU - Evavold, Brian D
AU  - Evavold BD
AUID- ORCID: 0000-0002-3561-3494
AD  - Department of Pathology, University of Utah School of Medicine, Salt Lake City, 
      UT 84132, USA.
FAU - Kwok, William W
AU  - Kwok WW
AUID- ORCID: 0000-0003-4843-4599
AD  - Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, 
      USA.
AD  - Department of Medicine, University of Washington, Seattle, WA 98195, USA.
LA  - eng
GR  - DP3 DK097653/DK/NIDDK NIH HHS/United States
GR  - DP3 DK106909/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190821
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (Autoantigens)
RN  - 0 (Epitopes)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DQ8 antigen)
SB  - IM
MH  - Alleles
MH  - Amino Acid Sequence
MH  - Autoantigens/*immunology
MH  - Cross Reactions/*immunology
MH  - Diabetes Mellitus, Type 1/etiology/metabolism
MH  - Epitopes/chemistry/immunology
MH  - HLA-DQ Antigens/chemistry/genetics/*immunology
MH  - Humans
MH  - Islets of Langerhans/*immunology
MH  - Models, Molecular
MH  - Protein Multimerization
MH  - Structure-Activity Relationship
MH  - T-Cell Antigen Receptor Specificity
MH  - T-Lymphocytes/*immunology/*metabolism
PMC - PMC6703875
EDAT- 2019/08/29 06:00
MHDA- 2020/05/08 06:00
PMCR- 2019/08/21
CRDT- 2019/08/29 06:00
PHST- 2019/02/07 00:00 [received]
PHST- 2019/07/11 00:00 [accepted]
PHST- 2019/08/29 06:00 [entrez]
PHST- 2019/08/29 06:00 [pubmed]
PHST- 2020/05/08 06:00 [medline]
PHST- 2019/08/21 00:00 [pmc-release]
AID - aaw9336 [pii]
AID - 10.1126/sciadv.aaw9336 [doi]
PST - epublish
SO  - Sci Adv. 2019 Aug 21;5(8):eaaw9336. doi: 10.1126/sciadv.aaw9336. eCollection 2019 
      Aug.