Comprehensive analysis of αβT-cell receptor repertoires reveals signatures of thymic selection

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F25%3A00143846" target="_blank" >RIV/00216224:14740/25:00143846 - isvavai.cz</a>

Result on the web

<a href="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605170/full" target="_blank" >https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605170/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fimmu.2025.1605170" target="_blank" >10.3389/fimmu.2025.1605170</a>

Result language

angličtina

Original language name

Comprehensive analysis of αβT-cell receptor repertoires reveals signatures of thymic selection

Original language description

Thymic selection is crucial for forming a pool of T-cells that can efficiently discriminate self from non-self using their T-cell receptors (TCRs) to develop adaptive immunity. In the present study we analyzed how a diverse set of physicochemical and sequence features of a TCR can affect the chances of successfully passing the selection. On a global scale we identified differences in selection probabilities based on CDR3 loop length, hydrophobicity, and residue sizes depending on variable genes and TCR chain context. We also observed a substantial decrease in N-glycosylation sites and other short sequence motifs for both alpha and beta chains. At the local scale we used dedicated statistical and machine learning methods coupled with a probabilistic model of the V(D)J rearrangement process to infer patterns in the CDR3 region that are either enriched or depleted during the course of selection. While the abundance of patterns containing poly-Glycines can improve CDR3 flexibility in selected TCRs, the "holes" in the TCR repertoire induced by negative selection can be related to Arginines in the (N)-Diversity (D)-N-region (NDN) region. Corresponding patterns were stored by us in a database available online. We demonstrated how TCR sequence composition affects lineage commitment during thymic selection. Structural modeling reveals that TCRs with "flat" and "bulged" CDR3 loops are more likely to commit T-cells to the CD4+ and CD8+ lineage respectively. Finally, we highlighted the effect of an individual MHC haplotype on the selection process, suggesting that those "holes" can be donor-specific. Our results can be further applied to identify potentially self-reactive TCRs in donor repertoires and aid in TCR selection for immunotherapies.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30102 - Immunology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Frontiers in immunology

ISSN

1664-3224

e-ISSN

—

Volume of the periodical

16

Issue of the periodical within the volume

Sep

Country of publishing house

CH - SWITZERLAND

Number of pages

14

Pages from-to

1-14

UT code for WoS article

001585920100001

EID of the result in the Scopus database

2-s2.0-105017833218