Table 2. Comparative overview of TCR... | Rockefeller University Press

Table 2.

Comparative overview of TCR triggering models and the unifying contribution of mechanobiology

Model	Mechanistic principle	Supporting evidence	Limitations	Mechanobiological integration	Ref.
Kinetic proofreading model	Signaling requires a minimum TCR: pMHC binding time and only persists while the TCR remains bound.	Explains antigen discrimination and how a single TCR bond with durable force can induce calcium flux.	Mechanism of how subtle differences in dwell time translate into strong signaling thresholds is unclear.	Force amplifies kinetic differences by extending bond lifetimes through catch-bond formation (∼10 pN).	(McKeithan, 1995)
Kinetic segregation model	Spatial exclusion of large phosphatases (e.g., CD45) from the TCR enables LCK-mediated phosphorylation of ITAMs.	Imaging studies showing spatial segregation of phosphatases during TCR engagement.	Passive size-based segregation alone may not fully account for signal initiation dynamics.	Both passive (TCR: pMHC bond) and active (catch bond/actin cytoskeleton) forces enhance phosphatase exclusion, promoting phosphorylation.	(Davis and van der Merwe, 2006) (James and Vale, 2012) (Chang et al., 2016)
Serial engagement model	A limited number of pMHCs serially bind to and trigger many TCRs through rapid association and dissociation cycles.	Functional assays show that cumulative temporary interactions can elicit robust calcium signaling.	Does not explain sustained signaling seen under high-force engagement.	Physiological shear forces optimize the balance between bond lifetime and turnover, allowing efficient serial triggering while maintaining sufficient signal duration.	(Valitutti, 2012) (Wofsy et al., 2001)
Allosteric/conformational change model	pMHC binding induces conformational rearrangements within the TCR, exposing ITAMs for phosphorylation.	Supported by FRET, NMR, and biochemical studies showing conformational shifts.	Static crystal structures of TCR: pMHC show minimal structural changes upon binding.	Mechanical load provides energy for conformational changes that may be undetectable in static structural analyses.	(Lee et al., 2004) (Beddoe et al., 2009)
Conformational change/lipid-release model	Upon TCR engagement, CD3 cytoplasmic tails dissociate from the inner lipid bilayer, exposing ITAMs to LCK.	Supported by biochemical and biophysical evidence.	Mechanism of linking extracellular ligand binding to intracellular tail release is not completely defined.	Forces transmitted through the TCR via the FG loop and transmembrane helices can pull CD3 tails away from the membrane, exposing ITAMs for phosphorylation.	(Xu et al., 2008) (Shi et al., 2013) (Guo et al., 2017)

Model	Mechanistic principle	Supporting evidence	Limitations	Mechanobiological integration	Ref.
Kinetic proofreading model	Signaling requires a minimum TCR: pMHC binding time and only persists while the TCR remains bound.	Explains antigen discrimination and how a single TCR bond with durable force can induce calcium flux.	Mechanism of how subtle differences in dwell time translate into strong signaling thresholds is unclear.	Force amplifies kinetic differences by extending bond lifetimes through catch-bond formation (∼10 pN).	(McKeithan, 1995)
Kinetic segregation model	Spatial exclusion of large phosphatases (e.g., CD45) from the TCR enables LCK-mediated phosphorylation of ITAMs.	Imaging studies showing spatial segregation of phosphatases during TCR engagement.	Passive size-based segregation alone may not fully account for signal initiation dynamics.	Both passive (TCR: pMHC bond) and active (catch bond/actin cytoskeleton) forces enhance phosphatase exclusion, promoting phosphorylation.	(Davis and van der Merwe, 2006)(James and Vale, 2012)(Chang et al., 2016)
Serial engagement model	A limited number of pMHCs serially bind to and trigger many TCRs through rapid association and dissociation cycles.	Functional assays show that cumulative temporary interactions can elicit robust calcium signaling.	Does not explain sustained signaling seen under high-force engagement.	Physiological shear forces optimize the balance between bond lifetime and turnover, allowing efficient serial triggering while maintaining sufficient signal duration.	(Valitutti, 2012)(Wofsy et al., 2001)
Allosteric/conformational change model	pMHC binding induces conformational rearrangements within the TCR, exposing ITAMs for phosphorylation.	Supported by FRET, NMR, and biochemical studies showing conformational shifts.	Static crystal structures of TCR: pMHC show minimal structural changes upon binding.	Mechanical load provides energy for conformational changes that may be undetectable in static structural analyses.	(Lee et al., 2004)(Beddoe et al., 2009)
Conformational change/lipid-release model	Upon TCR engagement, CD3 cytoplasmic tails dissociate from the inner lipid bilayer, exposing ITAMs to LCK.	Supported by biochemical and biophysical evidence.	Mechanism of linking extracellular ligand binding to intracellular tail release is not completely defined.	Forces transmitted through the TCR via the FG loop and transmembrane helices can pull CD3 tails away from the membrane, exposing ITAMs for phosphorylation.	(Xu et al., 2008)(Shi et al., 2013)(Guo et al., 2017)

TCR, T-cell receptor; pMHC, peptide–major histocompatibility complex; LCK, lymphocyte-specific protein tyrosine kinase; ITAMs, immunoreceptor tyrosine-based activation motifs; FRET, Förster resonance energy transfer; NMR, nuclear magnetic resonance.

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