1 / 37

TCR-MHC INTERACTIONS

TCR-MHC INTERACTIONS. September 2 7 , 200 6. Nathalie Labrecque Guy-Bernier Research Centre Maisonneuve-Rosemont Hospital nathalie.labrecque@umontreal.ca 252-3552. APC. CD8. MHC class I. peptide. a. b. V. V. a. b. C. C. TCR/CD3. e. d. g. e. CD3. CD3. CD3. CD3. z. z.

wayde
Télécharger la présentation

TCR-MHC INTERACTIONS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. TCR-MHC INTERACTIONS September 27, 2006 Nathalie Labrecque Guy-Bernier Research Centre Maisonneuve-Rosemont Hospital nathalie.labrecque@umontreal.ca 252-3552

  2. APC CD8 MHC class I peptide a b V V a b C C TCR/CD3 e d g e CD3 CD3 CD3 CD3 z z T cell

  3. How MHC class I and class II molecules bind peptides? Davis et al. 1998. Annu. Rev. Immunol. 16:523-544

  4. MHC-peptide structure

  5. -the variable portion of the TCR a and b chains is encoded by different gene segments -the TCR a and b locus are composed of multiple gene segments

  6. -random juxtaposition of V, D and J gene segments can generate a big number of different TCRs

  7. TCR diversity -random association of V, D and J -flexible joining of gene segments -N nucleotide addition - a and b association -no somatic hypermutation 1015 TCR

  8. LOCALIZATION OF DIVERSITY CDR1-CDR2: région V CDR3:junction V-J ou V-D-J CDR3 is hypervariable Davis et al. 1998. Annu. Rev. Immunol. 16:523-544

  9. Hennecke and Wiley. 2001. Cell 104:1-4

  10. Davis et al. 1998. Annu. Rev. Immunol. 16:523-544

  11. Peptide-MHC surfaces are not flat

  12. What are the constrainsts that fixed TCR-MHC-peptide orientation? • Conserved contacts between conserved portions of the TCR and MHC:NO • Shape of the TCR and/or peptide-MHC-binding surfaces limits the number of docking orientations:YES

  13. TRI-MOLECULAR COMPLEX CHARACTERISTICS -CDR1 eand CDR2 interact with MHC molecules (a helices) -CDR3 interacts with the peptide -interaction always in the same orientation -45 to 70 degrees angle related to peptide -Va see N-ter of the peptide -Vb see C-ter of the peptide

  14. Consistent features of TCR-MHC-peptide complex 1. Peptide contributes a smaller proportion of the buried surface area and a smaller number of contact than the MHC surface -peptide binding interface:21-34% -peptide proportion of contact:26-47% 2. Conformational flexibility -one or more of the CDR loops adopt different conformation -CDR3 loops show the greatest conformational changes

  15. Consequence of TCR affinity for its ligand During T cell development Mature T lymphocytes Goldrath and Bevan 1999. Nature 402:255-262

  16. T cell responses correlate very well with the binding characteristics of their TCRs • Higher affinity variants elicit more robust T cell responses • Increasing dissociation rates correlates with a decrease in agonistic activity • Antagonist peptides: differed only slightly in affinity with the weakest agonist but dissociation rate differed by 10-fold or more (increased)

  17. Physico-chemical characteristics of TCR-MHC-peptide interaction -On-rate ~1000 à 200 000 (binding speed) -Off-rate ~ 0.5-0.01s-1 ou t½ ~12-30s (dissociation speed) -KD ~1-50 mM (affinity) Correlation between the speed of dissociation and biological effect

  18. 1. Specificity 2. Sensibility 3. Context discrimination

  19. PARADOX -TCR-MHC interaction has a weak affinity -affinity ~ 10 mM -half-life ~10s -restricted numbers of ligands (~100) are displayed at the surface of antigen presenting cells -T cell activation requires a long interaction with antigen presenting cells (>2h)

  20. TCR engagement: challenge for activation -small size of the TCR -T cell surface is covered abundantly with big glycoproteins (LFA-1, CD48 ,CD45…) -weak affinity of the TCR for its ligand -half-life of the TCR-MHC complex is short (10s) -small number of specific peptide-MHC complex -T cells are moving -T cells must interact for long period with antigen presenting cells

  21. Proposed models to reconcile T cell sensitivity to Ag • Oligomerisation • Membrane microdomains (rafts) • Serial engagement • Immunological synapse • Binding in two-steps of the TCR to its ligand (sampling of MHC-peptide complexes at the surface of APCs) • Self-recognition sensitizes T cells

  22. Serial engagement (Valittuti et al. 1995. Nature 375:148-151) Tiré de Dustin and Cooper 2000. Nature Immunology 1:23-29

  23. Immunological synapse « SUPRAMOLECULAR ACTIVATION COMPLEX » Monks et al. 1998. Nature 395:82-86

  24. IMMUNOLOGICAL SYNAPSE Malissen 1999. 285:207-208

  25. La petite taille du RCT est requise pour une activation efficace des lymphocytes T Choudhuri K et al. 2005. Nature 436, 578-582

  26. La petite taille du RCT permet d’exclure les grosses molécules du centre de la synapse, incluant la phosphatase CD45 Choudhuri K et al. 2005. Nature 436, 578-582

  27. L’exclusion de la phosphatase CD45 des RCT engagés permet l’activation des lymphocytes T Choudhuri K et al. 2005. Nature 436, 578-582

  28. Two-steps binding of the TCR to its ligand - MHC residues (a helices) affect association (guide the TCR to its ligand) -allow conformational change of the CDR3 loops -peptide residues affect the dissociation or stability of the tri-molecular complex Tiré de Wu et al. 2002. Nature 418,552-556

  29. key and lock -initial association via CDR1 et CDR2 (on rate) -induces fitting of the CDR3 loops on the peptide (off rate) -stabilize the interaction allow an efficient scanning of the surface of Ag presenting cell to detect foreign peptide (rare and very similar to self) in a very sensitive manner

  30. APC CD8 MHC class I peptide soi TCR/CD3 a b V V T cell a b C C e d g e CD3 CD3 CD3 CD3 z z TCR-self-peptide-MHC interaction regulates T cell homeostasis -naive T lymphocyte survival -homeostatic proliferation (lymphopenia) « TCR tickling » -partial phosphorylation of z (p21) -ZAP-70 asociation to the TCR

  31. lck phosphoryles CD3 chains • recrutes ZAP-70 to the TCR/CD3 complex • ZAP phosphoryles different adaptors • adaptors propagate the signal to the main 3 signaling pathways • -ras-map kinase • -PLCg1 (calcineurin, PKC) • -PI-3K

  32. Lack of TCR-MHC-self peptide interaction abolished T cell reactivity to foreign Ag Tiré de Stefanova et al. 2002. Nature 420, 429-434

  33. Role of the TCR-MHC-self peptide interaction • MHC restriction • Naive T cell survival • Homeostatic proliferation • Increased T cell sensitivity to foreign peptides

  34. IMMUNOLOGICAL SYNAPSE facilitated by • Two steps binding (scanning) • Small size of the TCR (exclusion of CD45) • Increased sensitivity via self interactions • Rafts; colocalization of signaling molecules • Serial engagement ??? Allow for sensitive and specific T cell responses

More Related