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TCR-MHC INTERACTIONS. September 2 7 , 200 6. Nathalie Labrecque Guy-Bernier Research Centre Maisonneuve-Rosemont Hospital [email protected] 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. - PowerPoint PPT Presentation
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TCR-MHC INTERACTIONS
Nathalie LabrecqueGuy-Bernier Research CentreMaisonneuve-Rosemont [email protected]
September 27, 2006
TCR/CD3
CD8
V V
C CCD3CD3 CD3CD3
MHC class I
peptide
APC
T cell
How MHC class I and class II molecules bind peptides?
Davis et al. 1998. Annu. Rev. Immunol. 16:523-544
MHC-peptide structure
-the TCR and locus are composed of multiple gene segments
-the variable portion of the TCR and chains is encoded by different gene segments
-random juxtaposition of V, D and J gene segments can generate a big number of different TCRs
TCR diversity
-random association of V, D and J-flexible joining of gene segments-N nucleotide addition- and association-no somatic hypermutation
1015 TCR
LOCALIZATION OF DIVERSITY
CDR1-CDR2: région VCDR3:junction V-J ou V-D-J
CDR3 is hypervariable
Davis et al. 1998. Annu. Rev. Immunol. 16:523-544
Hennecke and Wiley. 2001. Cell 104:1-4
Davis et al. 1998. Annu. Rev. Immunol. 16:523-544
Peptide-MHC surfaces are not flat
What are the constrainsts that fixed TCR-MHC-peptide orientation?
1. Conserved contacts between conserved portions of the TCR and MHC:NO
2. Shape of the TCR and/or peptide-MHC-binding surfaces limits the number of docking orientations:YES
-CDR1 eand CDR2 interact with MHC molecules (helices)
-CDR3 interacts with the peptide
-interaction always in the same orientation-45 to 70 degrees angle related to peptide-V see N-ter of the peptide-V see C-ter of the peptide
TRI-MOLECULAR COMPLEX CHARACTERISTICS
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
Consequence of TCR affinity for its ligand
During T cell development
Mature T lymphocytes
Goldrath and Bevan 1999. Nature 402:255-262
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)
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 ~1-50M (affinity)
Correlation between the speed of dissociation and biological effect
1. Specificity
2. Sensibility
3. Context discrimination
PARADOX
-TCR-MHC interaction has a weak affinity-affinity ~ 10 M-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)
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
• 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
Proposed models to reconcile T cell sensitivity to Ag
Serial engagement
Tiré de Dustin and Cooper 2000. Nature Immunology 1:23-29
(Valittuti et al. 1995. Nature 375:148-151)
« SUPRAMOLECULAR ACTIVATION COMPLEX »
Monks et al. 1998. Nature 395:82-86
Immunological synapse
IMMUNOLOGICAL SYNAPSE
Malissen 1999. 285:207-208
La petite taille du RCT est requise pour une activation efficace des lymphocytes T
Choudhuri K et al. 2005. Nature 436, 578-582
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
L’exclusion de la phosphatase CD45 des RCT engagés permet l’activation des lymphocytes T
Choudhuri K et al. 2005. Nature 436, 578-582
Two-steps binding of the TCR to its ligand
- MHC residues ( 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
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
TCR-self-peptide-MHC interaction regulates T cell homeostasis -naive T lymphocyte survival-homeostatic proliferation (lymphopenia)
« TCR tickling » -partial phosphorylation of (p21) -ZAP-70 asociation to the TCR
TCR/CD3
CD8
V V
C CCD3CD3 CD3CD3
MHC class I
peptide
APC
T cell
soi
1. lck phosphoryles CD3 chains2. recrutes ZAP-70 to the TCR/CD3 complex3. ZAP phosphoryles different adaptors4. adaptors propagate the signal to the main 3 signaling pathways
-ras-map kinase-PLC1 (calcineurin, PKC)-PI-3K
Lack of TCR-MHC-self peptide interaction abolished T cell reactivity to foreign Ag
Tiré de Stefanova et al. 2002. Nature 420, 429-434
Role of the TCR-MHC-self peptide interaction
1. MHC restriction2. Naive T cell survival3. Homeostatic proliferation4. Increased T cell sensitivity to foreign peptides
IMMUNOLOGICAL SYNAPSE
facilitated by
1. Two steps binding (scanning)2. Small size of the TCR (exclusion of CD45)3. Increased sensitivity via self interactions4. Rafts; colocalization of signaling molecules5. Serial engagement ???
Allow for sensitive and specific T cell responses