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<p>During an immune response, T cells face one of the most consequential decisions of their lifespan&#xa0;upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal expansion and acquire effector functions. This process is often portrayed as a binary switch, in which naive cells from a highly diverse repertoire transition from an ‘off’ state to an ‘on’ state. However, this digital view overlooks the crucial prior information that T cells integrate through T cell receptor (TCR) interactions with self-peptide–MHC (self-pMHC). During thymic selection, immature T cells encounter a unique self-pMHC ligandome that shapes their development. After maturation, naive T cells continue to engage self-ligands as they patrol secondary lymphoid organs. Here we review evidence that these encounters with self-peptides are not only essential for T cell survival but also have lasting consequences that dynamically tune T cell function when called into action. The naive off state, therefore, is neither fixed nor functionally neutral. We argue that a deeper understanding of an individual’s self-peptide repertoire is crucial for deciphering TCR self and non-self discrimination&#xa0;and for effectively harnessing T cell responses to foreign antigens.</p>

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Calibrating T cell responsiveness through interactions with self

  • 期刊论文

  • 发表日期：

    2026年5月8日

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  • Judith N. Mandl,
  • Heather J. Melichar,
  • Byron B. Au-Yeung,
  • Johannes Textor,
  • Ludger Klein

摘要

During an immune response, T cells face one of the most consequential decisions of their lifespan upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal expansion and acquire effector functions. This process is often portrayed as a binary switch, in which naive cells from a highly diverse repertoire transition from an ‘off’ state to an ‘on’ state. However, this digital view overlooks the crucial prior information that T cells integrate through T cell receptor (TCR) interactions with self-peptide–MHC (self-pMHC). During thymic selection, immature T cells encounter a unique self-pMHC ligandome that shapes their development. After maturation, naive T cells continue to engage self-ligands as they patrol secondary lymphoid organs. Here we review evidence that these encounters with self-peptides are not only essential for T cell survival but also have lasting consequences that dynamically tune T cell function when called into action. The naive off state, therefore, is neither fixed nor functionally neutral. We argue that a deeper understanding of an individual’s self-peptide repertoire is crucial for deciphering TCR self and non-self discrimination and for effectively harnessing T cell responses to foreign antigens.