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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.

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TCR-MHC INTERACTIONS

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  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

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