Kinetic-segregation model of T cell activation

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Kinetic-segregation is a model proposed for the mechanism of T-cell receptor (TCR) triggering. [1] [2] It offers an explanation for how TCR binding to its ligand triggers 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.

Contents

Mechanism

On plasma membrane of a T cell there is the T-cell receptor (consists of α,β chains and multiple CD3 adaptor proteins), as well as molecules that induce signalling (tyrosine kinase Lck phosphorylates ITAMs in CD3 complex) and factors that inhibit signalling (tyrosine phosphatases 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-MHC complex, formed when a T cell recognises its ligand on an antigen presenting cell (APC) and the T-cell-APC contact occurs, spans a short length. This results in the formation of close contact zones between the membranes of the T cell and antigen presenting cell (~15 nm apart) around the TCR/peptide-MHC complex. [3] Phosphatases CD45 and CD148 with much larger ectodomains than TCR are sterically excluded from the close contact zones, while the region is still accessible for the small kinase Lck. This perturbs the balance of kinase activity to phosphatase activity and ITAM phosphorylation is strongly favoured. [3] Such prolonged phosphorylation of ITAMs by Lck kinase allows time for ZAP-70 recruitment, its activation by phosphorylation and subsequent phosphorylation of adaptor proteins LAT and 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 conventional and superagonistic (mitogenic) antibodies in suspension does not constrict the dephosphorylation effect of phosphatases acting on CD28. However, when these antibodies are immobilized (either by secondary antibody bound to plastic or by Fc receptors on other cells) considerable 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

Related Research Articles

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<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions.

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<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

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<span class="mw-page-title-main">Lck</span> Lymphocyte protein

Lck is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T-cell receptor signaling in both naive T cells and effector T cells. The role of the Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the role of the lck varies among the memory T cells subsets. It seems that in mice, in the effector memory T cells (TEM) population, more than 50% of lck is present in a constitutively active conformation, whereas, only less than 20% of lck is present as active form of lck. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

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<span class="mw-page-title-main">CD22</span> Lectin molecule

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<span class="mw-page-title-main">CD5 (protein)</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PTPN22</span>

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<span class="mw-page-title-main">Signal-regulatory protein alpha</span>

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A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

<span class="mw-page-title-main">Tyrosine phosphorylation</span> Phosphorylation of peptidyl-tyrosine

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References

  1. ↑ Murphy, Kenneth (2017). Janeway's immunobiology (9th ed.). New York. p. 268. ISBN   978-0815345510.
  2. ↑ van der Merwe, PA; Dushek, O (January 2011). "Mechanisms for T cell receptor triggering". Nature Reviews. Immunology. 11 (1): 47–55. doi:10.1038/nri2887. PMID   21127503. S2CID   22423010.
  3. 1 2 3 4 Davis, SJ; van der Merwe, PA (August 2006). "The kinetic-segregation model: TCR triggering and beyond". Nature Immunology. 7 (8): 803–9. doi:10.1038/ni1369. PMID   16855606. S2CID   11631728.
  4. ↑ Varma, R; Campi, G; Yokosuka, T; Saito, T; Dustin, ML (July 2006). "T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster". Immunity. 25 (1): 117–27. doi:10.1016/j.immuni.2006.04.010. PMC   1626533 . PMID   16860761.
  5. ↑ Lin, J; Weiss, A (18 August 2003). "The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling". The Journal of Cell Biology. 162 (4): 673–82. doi: 10.1083/jcb.200303040 . PMC   2173795 . PMID   12913111.
  6. ↑ Irles, C; Symons, A; Michel, F; Bakker, TR; van der Merwe, PA; Acuto, O (February 2003). "CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling". Nature Immunology. 4 (2): 189–97. doi:10.1038/ni877. PMID   12496963. S2CID   31201077.
  7. ↑ Choudhuri, K; Parker, M; Milicic, A; Cole, DK; Shaw, MK; Sewell, AK; Stewart-Jones, G; Dong, T; Gould, KG; van der Merwe, PA (18 September 2009). "Peptide-major histocompatibility complex dimensions control proximal kinase-phosphatase balance during T cell activation". The Journal of Biological Chemistry. 284 (38): 26096–105. doi: 10.1074/jbc.M109.039966 . PMC   2758009 . PMID   19628870.
  8. ↑ Choudhuri, K; Wiseman, D; Brown, MH; Gould, K; van der Merwe, PA (28 July 2005). "T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand". Nature. 436 (7050): 578–82. Bibcode:2005Natur.436..578C. doi:10.1038/nature03843. PMID   16049493. S2CID   4319128.
  9. 1 2 Bluemel, C; Hausmann, S; Fluhr, P; Sriskandarajah, M; Stallcup, WB; Baeuerle, PA; Kufer, P (August 2010). "Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen". Cancer Immunology, Immunotherapy. 59 (8): 1197–209. doi:10.1007/s00262-010-0844-y. PMID   20309546. S2CID   10279696.
  10. ↑ James, SE; Greenberg, PD; Jensen, MC; Lin, Y; Wang, J; Till, BG; Raubitschek, AA; Forman, SJ; Press, OW (15 May 2008). "Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane". Journal of Immunology. 180 (10): 7028–38. doi: 10.4049/jimmunol.180.10.7028 . PMC   2585549 . PMID   18453625.
  11. ↑ Geppert, TD; Lipsky, PE (15 March 1987). "Accessory cell independent proliferation of human T4 cells stimulated by immobilized monoclonal antibodies to CD3". Journal of Immunology. 138 (6): 1660–6. doi:10.4049/jimmunol.138.6.1660. PMID   3102594. S2CID   26874072.
  12. ↑ Ma, Z; Sharp, KA; Janmey, PA; Finkel, TH (February 2008). "Surface-anchored monomeric agonist pMHCs alone trigger TCR with high sensitivity". PLOS Biology. 6 (2): e43. doi: 10.1371/journal.pbio.0060043 . PMC   2253636 . PMID   18303949.
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