Kinetic-segregation model of T cell activation

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Kinetic-segregation is a model proposed for the mechanism of

T-cell activation, based on size-sensitivity for the molecules involved. Simon J. Davis and Anton van der Merwe, University of Oxford
, proposed this model in 1996. According to the model, TCR signalling is initiated by segregation of phosphatases with large extracellular domains from the TCR complex when binding to its ligand, allowing small kinases to phosphorylate intracellular domains of the TCR without inhibition. Its might also be applicable to other receptors of the Non-catalytic tyrosine-phosphorylated receptors family such as CD28.

Mechanism

On plasma membrane of a T cell there is the T-cell receptor (consists of α,β chains and multiple

CD45 and CD148). In the resting T-cell, all molecules are repeatedly colliding by means of diffusion
. The TCR/CD3 complex is constantly being phosphorylated by Lck. Because of an abundance of CD45 and CD148 in the cell membrane, phosphorylations are readily removed before they can recruit downstream signalling molecules. Overall phosphorylation of the TCR is low and tonic TCR signalling is avoided.[3]

The TCR/peptide-

SLP-76. Full T-cell activation is initiated by multiple triggering events described above. When T-cell and APC membranes separate, the close-contact zone vanishes and large-ectodomain tyrosine phosphatases are allowed to restore the ground state.[3]

Supporting evidence

During ligand binding, CD45 and CD148 are excluded from the TCR region.[4][5] It was also shown that both the truncation of CD45 and CD148 (hence are able to enter the close contact zone) and the elongation of the MHC inhibit TCR triggering.[6][7][8][9] Furthermore CAR cell function is affected by the size of the ligand it recognises.[9][10] Finally, T cells can be activated by pMHC immobilised on a plate surface but not by soluble, monomeric pMHC, providing evidence that TCR triggering depends on restricting width between two membranes.[11][12]

Kinetic segregation as model for other signalling receptors

Antibody-induced signaling by CD28

In the resting T-cell there is no net phosphorylation of CD28 (one of the molecules providing co-stimulatory signals required for T-cell activation). Kinetic-segregation model uses here the same explanation as it provides for low net phosphorylation of TCR in the resting T-cell described previously.

Binding of both

steric
constraints emerge. It is of note, that the immobilized conventional antibody poses less prominent spatial constraints than the immobilized superagonistic antibody. CD45 phosphatase is not completely excluded from the close-contact zone and thus the signal generated in the case of a conventional antibody is weaker. Immobilized superagonistic antibodies bound to CD28 exclude CD45 phosphatases completely and the signal leading to T-cell activation is stronger.

Further applications

The tyrosine kinase Lck functions either in conjunction with a co-receptor molecule (CD4 or CD8) or as a free Lck kinase. The kinetic-segregation model might be applied to both co-receptor dependent and co-receptor independent signaling through TCR.

See also

References

  1. ISBN 978-0815345510.{{cite book}}: CS1 maint: location missing publisher (link
    )
  2. S2CID 22423010
    .
  3. ^
    S2CID 11631728
    .
  4. PMID 16860761
    .
  5. PMID 12913111
    .
  6. S2CID 31201077
    .
  7. PMID 19628870
    .
  8. S2CID 4319128
    .
  9. ^
    S2CID 10279696
    .
  10. PMID 18453625
    .
  11. S2CID 26874072
    .
  12. PMID 18303949
    .
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