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Adhesion? Sticking & Signalling

Adhesion? Sticking & Signalling. E. Yvonne Jones Erice 2006. T cell – target cell interactions, a particular form of cell-cell communication with specificity contributed by pMHC – TCR binding. Result: T cell receptor (TCR) signalling and formation of an ‘Immunological Synapse’.

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Adhesion? Sticking & Signalling

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  1. Adhesion? Sticking & Signalling E. Yvonne Jones Erice 2006

  2. T cell – target cell interactions, a particular form of cell-cell communication with specificity contributed by pMHC – TCR binding. Result: T cell receptor (TCR) signalling and formation of an ‘Immunological Synapse’.

  3. But, all pMHCs are not equal… Immunodominant HLA-A2 tumour epitope NY-ESO-1157-165: SLLMWITQC SLLMWITQV stimulates faster polarisation of lytic granules to the immunological synapse Chen & Stewart-Jones et al (2005) J. Exp. Med.201 1243-1255

  4. and all TCRs are not equal… Structure of the immunodominant bV17-aV10s2 T cell receptor with HLA A2/influenza matrix epitope …..as used by >one billion humans! Stewart-Jones et al (2003) Nature Immunol.4 657-663

  5. Vβ17 Flu Matrix T Cells- The Most Abundant T cell Clonotype on the Planet • An estimated 3 billion people have HLA-A2 • All have had Influenza • Flu matrix responses dominate the immune reaction to infection • Vβ17 clonotype constitutes > 80% of that response • 0.5 kg of this receptor circulating in the world • Stacking the receptors end-to-end would stretch more than halfway to Neptune (2.6 billion km) Guillaume Stewart-Jones, Jeffrey Ishizuka & John Bell, unpublished calculation

  6. Why is a bV17-aV10s2 TCR so good at recognising HLA A2/influenza matrix epitope?

  7. Kuby, 4th edition

  8. The potential TCR repertoire is further increased • by the addition of N region nucleotides. The recombination process is not precise. • the exact points of splicing between V, D and J regions can vary over • several nucleotides • • extra nucleotides, called N regions, can also be inserted at these joints. • The number of TCRs that we make is ~2.5 x 107

  9. The challenge Flu matrix peptide presented by HLA-A2 provides few sidechains for TCR recognition

  10. The answer TCR positioned to insert CRD3b between peptide and alpha 2 helix

  11. Why is a bV17-aV10s2 TCR so good at recognising HLA A2/influenza matrix epitope? Its because of a distinctive CDR3b motif and combination of residues unique to bV17-aV10s2 CDR1 and CDR2 loops that allow the CDR3b to be positioned optimally to sample a unique feature of the pMHC surface Stewart-Jones et al (2003) Nature Immunol. 4, 657-663

  12. sTCR mutants made and tested Jeffrey Ishizuka & Guillaume Stewart-Jones

  13. Vβ17 CDR2 Offers a Unique Sequence and Energetic Landscape

  14. So we are still on target with our hypothesis for why a bV17-aV10s2 TCR is so good at recognising HLA A2/influenza matrix epitope. But why is this TCR-pMHC immunodominant over all other TCR-pMHC interactions involving influenza virus epitopes presented by the MHC class I molecule HLA A2?

  15. T cell – target cell interactions, a particular form of cell-cell communication with specificity contributed by pMHC – TCR binding. Result: T cell receptor (TCR) signalling and formation of an ‘Immunological Synapse’.

  16. S S S S S S S S S S S S S S S S S S S S S S S S RPTPg PTPg-S RPTPb/z Phosphacan 1 2 DPTP10D CRYP2 DPTP99A CRYPa RPTPs LAR RPTPd PTP-BR7/SL RPTPm RPTPk RPTPl RPTPa RPTPe CD45 PTP-IA2 DPTP69D DLAR VII V IIA Type I IIB III IV VI catalytic PTP domain Highly glycosilated domain S Ig-like domain Cys-rich domain S carbonic anhydrase- related domain MAM domain FN-III-like domain related to cadherin intracellular region protease cleavage site Receptor protein tyrosine phosphatases: classification

  17. S S A C D B RPTPm is a cell-adhesion molecule involved in neural development (axon growth) and angiogenesis. RPTPm RPTPm expression on axonal growth cones (A and B, Ledig et al., 1999) and at the endothelial cell junctions (C and D, Bianchi et al., 1999).

  18. RPTPm RPTPm RPTPm N N N S S S S S S MAM-Ig S S C C C Crystal structure of the MAM-Ig unit Aricescu & Hon (2006) EMBO J. 25 701-712 structure function? NO for dimers need MIg-FNIII and for adhesion need MIg-2xFNIII so… *

  19. MIg structure plus biophysical and functional data generated several possible models for RPTPm adhesive interactions I recommend you go and see Radu Aricescu’s poster in the Thursday afternoon session (also Christian Siebold’s poster on cell guidance signalling…) Zipper model, consistent with the extended planarity of the plasma membrane observed at intercellular contact sites and with the multiple interactions observed between RPTPm ectodomains pH-dependent dimer (trans) trans/trans zipper monomer trans/cis zipper * *

  20. Christian Siebold Weixian Lu (Jeffrey Ishizuka) & Guillaume Stewart-Jones Radu Aricescu In collaboration with: John Bell, Vincenzo Cerundolo, Andrew McMichael & Anton van der Merwe

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