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

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

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCRα to TCRβ chains with the estimated total TCR diversity of >108. Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self- and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4+ compartment TCRα chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCRα chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCRα chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCRα chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCRβ repertoire associated with these chains.

Original languageEnglish
Article number102616
JournalJOURNAL OF AUTOIMMUNITY
Volume119
DOIs
Publication statusPublished - May 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • Autoantigen
  • Autoimmunity
  • T cell receptor
  • T cell recombination
  • Thymic selections
  • Thymus

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