Genetic bias, diversity indices, physiochemical properties and CDR3 motifs divide auto-reactive from allo-reactive T-Cell repertoires

Haigh, Oscar L., Grant, Emma J., Nguyen, Thi H.O., Kedzierska, Katherine, Field, Matt A., and Miles, John J. (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 (4). 1625.

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Abstract

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.

Item ID: 66025
Item Type: Article (Research - C1)
ISSN: 1422-0067
Keywords: T-cell; T-cell receptor; T-cell repertoire; T-cell alloreactivity
Copyright Information: Copyright: © 2021 by the authors. License MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Funders: Prostate Cancer Foundation Australia (PCFA), National and Medical Research Council of Australia (NHMRC), Australian Research Council (ARC)
Projects and Grants: PCFA Research Grant (NCG 3913), NHMRC C.J Martin Fellowship (1110429), ARC DECRA Fellowship (DE210101479), NHMRC Leadership Investigator Grant (1173871), NHMRC fellowship (5121190), NHMRC Fellowship (1031652), NHMRC Fellowship (1131732)
Date Deposited: 17 Feb 2021 02:50
FoR Codes: 31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310206 Sequence analysis @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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