Calibrating T cell responsiveness through interactions with self.

Self-peptide-MHC interactions dynamically tune naive T cell responsiveness, showing the naive “off” state is not fixed or functionally neutral during immune decisions.

• Why it matters: A binary “off-to-on” model misses how prior self-peptide information is integrated, limiting understanding of TCR self versus non-self discrimination and effective T cell targeting.
• What they did: The review synthesizes evidence that thymic selection and ongoing patrol in secondary lymphoid organs involve TCR engagement with self-pMHC, shaping survival and later effector tuning.
• The result: These self encounters are linked to lasting, dynamic calibration of T cell function upon activation, implying that an individual’s self-peptide repertoire is key for interpreting and harnessing responses to foreign antigens.

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