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<p>T cells use their T-cell receptors (TCRs) to discriminate between higher-affinity foreign and lower-affinity self-peptide-MHC (pMHC) antigen complexes. The OT-I mouse TCR is widely used to study antigen discrimination between foreign and self-pMHC antigens, and previous work suggested it achieved near-perfect discrimination between higher- and lower-affinity antigens. However, other TCRs show imperfect discrimination. To resolve these discrepancies, we developed in this study a protocol for measuring ultra-low TCR-pMHC binding affinities to determine the 3D solution affinities of OT-I TCR for 19 pMHCs. These revised 3D affinities now strongly correlate with 2D membrane affinities and predict T-cell functional responses. Our results indicate that OT-I exhibits enhanced yet imperfect discrimination, similar to other TCRs, explaining how T cells can detect abnormally high levels of low-affinity self-antigens. We also show that OT-I discrimination is consistent with the kinetic proofreading model, which highlights that discrimination is most effective for low-affinity pMHC ligands. Our work underscores the ability of T cells to gauge proxies for 3D affinity within the 2D interface, with implications for the mechanisms underlying antigen discrimination.</p>

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Murine T-cell receptor OT-I exhibits imperfect discrimination between foreign and self-antigens

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Anna Huhn,
  • Mikhail A Kutuzov,
  • Keir Maclean,
  • Lion F K Uhl,
  • Jagdish M Mahale,
  • Audrey Gérard,
  • P Anton van der Merwe,
  • Omer Dushek

摘要

T cells use their T-cell receptors (TCRs) to discriminate between higher-affinity foreign and lower-affinity self-peptide-MHC (pMHC) antigen complexes. The OT-I mouse TCR is widely used to study antigen discrimination between foreign and self-pMHC antigens, and previous work suggested it achieved near-perfect discrimination between higher- and lower-affinity antigens. However, other TCRs show imperfect discrimination. To resolve these discrepancies, we developed in this study a protocol for measuring ultra-low TCR-pMHC binding affinities to determine the 3D solution affinities of OT-I TCR for 19 pMHCs. These revised 3D affinities now strongly correlate with 2D membrane affinities and predict T-cell functional responses. Our results indicate that OT-I exhibits enhanced yet imperfect discrimination, similar to other TCRs, explaining how T cells can detect abnormally high levels of low-affinity self-antigens. We also show that OT-I discrimination is consistent with the kinetic proofreading model, which highlights that discrimination is most effective for low-affinity pMHC ligands. Our work underscores the ability of T cells to gauge proxies for 3D affinity within the 2D interface, with implications for the mechanisms underlying antigen discrimination.