Generation of self-reactive, shared T-cell receptor α chains in the human thymus

Heikkilä, Nelli; Sormunen, Silja; Mattila, Joonatan; Härkönen, Taina; Knip, Mikael; Ihantola, Emmi Leena; Kinnunen, Tuure; Mattila, Ilkka; Saramäki, Jari; Arstila, T. Petteri

doi:10.1016/j.jaut.2021.102616

Cited by 8 publications

(11 citation statements)

References 54 publications

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“…This shared, or public TCRα repertoire also contains numerous chains that have been linked in earlier studies to the recognition of specific antigens, both self and nonself 14–16 . Interestingly, our data also showed that TCRα chains associated with reactivity to pancreatic islet self‐antigens are not deleted in the thymus, nor diverted to the regulatory lineage 17 . This suggests that for some self‐antigens, at least, negative selection may not be particularly stringent.…”

Section: Introductionsupporting

confidence: 73%

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Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens

et al. 2023

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Background The number of mutations in cancer cells is an important predictor of a positive response to cancer immunotherapy. It has been suggested that the neoantigens produced by these mutations are more immunogenic than nonmutated tumor antigens, which are likely to be protected by immunological tolerance. However, the mechanisms of tolerance as regards tumor antigens are incompletely understood. Methods Here, we have analyzed the impact of thymic negative selection on shared T‐cell receptor (TCR) repertoire associated with the recognition of either mutated or nonmutated tumor antigens by comparing previously known TCR—antigen—pairs to TCR repertoires of 21 immunologically healthy individuals. Results Our results show that TCRα chains associated with either type of tumor antigens are readily generated in the thymus, at a frequency similar to TCRα chains associated with nonself. In the peripheral repertoire, the relative clone size of nonself‐associated chains is higher than that of the tumor antigens, but importantly, there is no difference between TCRα chains associated with mutated or nonmutated tumor antigens. Conclusion This suggests that the tolerance mechanisms protecting nonmutated tumor antigens are non‐deletional and therefore potentially reversible. As unmutated antigens are, unlike mutations, shared by a large number of patients, they may offer advantages in designing immunological approaches to cancer treatment.

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Section: Introductionsupporting

confidence: 73%

“…The study was done according to the principles of the Declaration of Helsinki. The details of the samples and the sequencing data have been previously published 17 . (Table S1).…”

Section: Methodsmentioning

confidence: 99%

Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens

et al. 2023

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“…The effect of the HLA genotype on the repertoire of CDR3 beta sequences is detectable ( Khosravi-Maharlooei et al., 2019 ; Tanno et al., 2020 ) but remains relatively small ( Emerson et al., 2017 ; Heikkilä et al., 2021 ; Pogorelyy et al., 2018 ; Springer et al., 2021 ). This is explained at least in part by the fact that most MHC-associated peptides can bind to multiple HLA alleles.…”

Section: Discussionmentioning

confidence: 99%

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Trofimov¹,

Brouillard²,

Séguin³

et al. 2022

iScience

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“…The effect of the HLA genotype on the repertoire of CDR3 beta sequences is detectable (Khosravi-Maharlooei et al, 2019; Tanno et al, 2020) but remains reatively small (Emerson et al, 2017; Heikkilä et al, 2021; Pogorelyy et al, 2018; Springer et al, 2021). This is explained at least in part by the fact that most MHC-associated peptides can bind to multiple HLA alleles.…”

Section: Discussionmentioning

confidence: 99%

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Trofimov

Brouillard

Séguin

et al. 2022

Preprint

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SUMMARYBased on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist throughout life, are highly shared among subjects, and are polyreactive to self and microbial antigens. Thus, >50% of cord blood TCRs are responsive to SARS-CoV2 and other common pathogens. TDT- dependent TCRs present distinct structural features and are less shared among subjects. TDT- dependent TCRs are produced in maximal numbers during infancy when thymic output and TDT activity reach a summit, are more abundant in subjects with AIRE mutations, and seem to play a dominant role in graft-versus-host disease. Factors decreasing thymic output (age, male sex) negatively impact TCR diversity. Males compensate for their lower repertoire diversity via hyperexpansion of selected TCR clonotypes.

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Generation of self-reactive, shared T-cell receptor α chains in the human thymus

Cited by 8 publications

References 54 publications

Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens

Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Two types of human TCR differentially regulate reactivity to self and non-self antigens

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