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Article

Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires

1
Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB), Commissariat à l’Énergie Atomique et aux Énergies renouvelables, Université Paris-Saclay, INSERM U1184, Fontenay-aux-Roses, France
2
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
3
Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, Australia
4
The Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Cairns, QLD 4811, Australia
5
Centre for Molecular Therapeutics, James Cook University, Cairns, QLD 4811, Australia
6
Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Cairns, QLD 4811, Australia
7
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
8
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Jeffrey L. Platt
Int. J. Mol. Sci. 2021, 22(4), 1625; https://doi.org/10.3390/ijms22041625
Received: 4 December 2020 / Revised: 30 January 2021 / Accepted: 31 January 2021 / Published: 5 February 2021
(This article belongs to the Special Issue Recent Advances in T Cell Immunity)
The distinct properties of allo-reactive T-cell repertoires are not well understood. To investigate whether auto-reactive and allo-reactive T-cell repertoires encoded distinct properties, we used dextramer enumeration, enrichment, single-cell T-cell receptor (TCR) sequencing and multiparameter analysis. We found auto-reactive and allo-reactive T-cells differed in mean ex vivo frequency which was antigen dependent. Allo-reactive T-cells showed clear differences in TCR architecture, with enriched usage of specific T-cell receptor variable (TRBJ) genes and broader use of T-cell receptor variable joining (TRBJ) genes. Auto-reactive T-cell repertoires exhibited complementary determining regions three (CDR3) lengths using a Gaussian distribution whereas allo-reactive T-cell repertoires exhibited distorted patterns in CDR3 length. CDR3 loops from allo-reactive T-cells showed distinct physical-chemical properties, tending to encode loops that were more acidic in charge. Allo-reactive T-cell repertoires differed in diversity metrics, tending to show increased overall diversity and increased homogeneity between repertoires. Motif analysis of CDR3 loops showed allo-reactive T-cell repertoires differed in motif preference which included broader motif use. Collectively, these data conclude that allo-reactive T-cell repertoires are indeed different to auto-reactive repertoires and provide tangible metrics for further investigations and validation. Given that the antigens studied here are overexpressed on multiple cancers and that allo-reactive TCRs often show increased ligand affinity, this new TCR bank also has translational potential for adoptive cell therapy, soluble TCR-based therapy and rational TCR design. View Full-Text
Keywords: T-cell; T-cell receptor; T-cell repertoire; T-cell alloreactivity T-cell; T-cell receptor; T-cell repertoire; T-cell alloreactivity
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MDPI and ACS Style

Haigh, O.L.; Grant, E.J.; Nguyen, T.H.O.; Kedzierska, K.; Field, M.A.; Miles, J.J. Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires. Int. J. Mol. Sci. 2021, 22, 1625. https://doi.org/10.3390/ijms22041625

AMA Style

Haigh OL, Grant EJ, Nguyen THO, Kedzierska K, Field MA, Miles JJ. Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires. International Journal of Molecular Sciences. 2021; 22(4):1625. https://doi.org/10.3390/ijms22041625

Chicago/Turabian Style

Haigh, Oscar L., Emma J. Grant, Thi H.O. Nguyen, Katherine Kedzierska, Matt A. Field, and John J. Miles 2021. "Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires" International Journal of Molecular Sciences 22, no. 4: 1625. https://doi.org/10.3390/ijms22041625

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