PMID- 34845983
OWN - NLM
STAT- MEDLINE
DCOM- 20211209
LR  - 20231103
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 10
DP  - 2021 Nov 30
TI  - TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification 
      of public, HLA-restricted clusters of SARS-CoV-2 TCRs.
LID - 10.7554/eLife.68605 [doi]
LID - e68605
AB  - T-cell receptors (TCRs) encode clinically valuable information that reflects 
      prior antigen exposure and potential future response. However, despite advances 
      in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR 
      clonotypes as clinical biomarkers. We propose a new framework that leverages 
      experimentally inferred antigen-associated TCRs to form meta-clonotypes - groups 
      of biochemically similar TCRs - that can be used to robustly quantify 
      functionally similar TCRs in bulk repertoires across individuals. We apply the 
      framework to TCR data from COVID-19 patients, generating 1831 public TCR 
      meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong 
      evidence of restriction to patients with a specific human leukocyte antigen (HLA) 
      genotype. Applied to independent cohorts, meta-clonotypes targeting these 
      specific epitopes were more frequently detected in bulk repertoires compared to 
      exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 
      patients that expressed the putative restricting HLA allele (false discovery rate 
      [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as 
      antigen-specific features for biomarker development. To enable further 
      applications, we developed an open-source software package, tcrdist3, that 
      implements this framework and facilitates flexible workflows for distance-based 
      TCR repertoire analysis.
CI  - (c) 2021, Mayer-Blackwell et al.
FAU - Mayer-Blackwell, Koshlan
AU  - Mayer-Blackwell K
AUID- ORCID: 0000-0002-1652-4023
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, United States.
FAU - Schattgen, Stefan
AU  - Schattgen S
AD  - Department of Immunology, St Jude Children's Research Hospital, Memphis, United 
      States.
FAU - Cohen-Lavi, Liel
AU  - Cohen-Lavi L
AD  - Department of Industrial Engineering and Management, Ben-Gurion University of the 
      Negev, Be'er Sheva, Israel.
FAU - Crawford, Jeremy C
AU  - Crawford JC
AD  - Department of Immunology, St Jude Children's Research Hospital, Memphis, United 
      States.
FAU - Souquette, Aisha
AU  - Souquette A
AD  - St Jude Children's Research Hospital, Memphis, United States.
FAU - Gaevert, Jessica A
AU  - Gaevert JA
AD  - Department of Immunology, St Jude Children's Research Hospital, Memphis, United 
      States.
FAU - Hertz, Tomer
AU  - Hertz T
AD  - Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of 
      the Negev, Be'er Sheva, United States.
FAU - Thomas, Paul G
AU  - Thomas PG
AD  - St Jude Children's Research Hospital, Memphis, United States.
FAU - Bradley, Philip
AU  - Bradley P
AUID- ORCID: 0000-0002-0224-6464
AD  - Fred Hutchinson Cancer Research Center, Seattle, United States.
FAU - Fiore-Gartland, Andrew
AU  - Fiore-Gartland A
AUID- ORCID: 0000-0001-7627-2166
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, United States.
LA  - eng
GR  - R01 AI136514/AI/NIAID NIH HHS/United States
GR  - S10 OD028685/OD/NIH HHS/United States
GR  - ORIP S10OD028685/NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211130
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Antigens, Viral)
RN  - 0 (Biomarkers)
RN  - 0 (Complementarity Determining Regions)
RN  - 0 (Epitopes)
RN  - 0 (HLA Antigens)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
UOF - bioRxiv. 2021 Mar 19;:. PMID: 33398288
MH  - Antigens, Viral/*genetics/immunology
MH  - Biomarkers
MH  - COVID-19/genetics/*immunology
MH  - Complementarity Determining Regions/immunology
MH  - Computational Biology/methods
MH  - Epitopes/genetics/immunology
MH  - Genotype
MH  - HLA Antigens/*genetics/immunology
MH  - Humans
MH  - Receptors, Antigen, T-Cell/*genetics/immunology
MH  - SARS-CoV-2/*immunology
PMC - PMC8631793
OTO - NOTNLM
OT  - SARS-CoV-2
OT  - T cell receptor
OT  - biomarkers
OT  - computational biology
OT  - human
OT  - immune repertoire
OT  - immunology
OT  - inflammation
OT  - software
OT  - systems biology
COIS- KM, SS, LC, AS, JG, AF No competing interests declared, JC JCC served as unpaid 
      consultant for 10X Genomics on the initial analysis of the 10x_200k dataset. TH 
      TH has equity in Poold Diagnostics. PT is on the Scientific Advisory Boards of 
      Immunoscape and Cytoagents, consulted for Elevate Bio and PACT Pharma, and has 
      received travel costs and speaking fees from 10X Genomics and Illumina. PT served 
      as unpaid consultant for 10X Genomics on the initial analysis of the 10x_200k 
      dataset. PT also has filed patents on methods for sequencing and cloning TCRs 
      (International PCT applications published December 24, 2020 as WO 2020/257575 and 
      January 7, 2021 as WO 2021/003114). These applications are pending and have not 
      yet been granted. PB served as unpaid consultant for 10X Genomics on the initial 
      analysis of the 10x_200k dataset.
EDAT- 2021/12/01 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/11/30
CRDT- 2021/11/30 08:46
PHST- 2021/03/20 00:00 [received]
PHST- 2021/11/11 00:00 [accepted]
PHST- 2021/11/30 08:46 [entrez]
PHST- 2021/12/01 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/11/30 00:00 [pmc-release]
AID - 68605 [pii]
AID - 10.7554/eLife.68605 [doi]
PST - epublish
SO  - Elife. 2021 Nov 30;10:e68605. doi: 10.7554/eLife.68605.