Cellule souche Un double système,cellulaire et moléculaire de reconnaissance de l’antigène Bourse de Fabricius Ou moelle osseuse Organe de différenciation.

Présentation au sujet: "Cellule souche Un double système,cellulaire et moléculaire de reconnaissance de l’antigène Bourse de Fabricius Ou moelle osseuse Organe de différenciation."— Transcription de la présentation:

1 Cellule souche Un double système,cellulaire et moléculaire de reconnaissance de l’antigène Bourse de Fabricius Ou moelle osseuse Organe de différenciation thymus B cell CD3 T cell TCR BcR = immunoglobulines Récepteurs clonaux Peptide issu de l’antigène MHC Antigène entier Antigène (protéine bactérienne)

2 La bonne coopération T – B requiert que les 2 partenaires :
Pour fabriquer des quantités optimales d’Ac affins, Les cellules B doivent avoir coopérer directement Avec les cellules T Cellule B CelluleT La bonne coopération T – B requiert que les 2 partenaires : Développent des contacts directs Soient spécifiques du même Ag aient été préactivés par un 3° partenaire cellulaire

3 La coopération cellules T- cellules B,
Un long ballet avec de nombreux partenaires 50 années de coopération T – B : La question du pont antigènique 2. Les évènements cellulaires ; la réaction du centre germinatif. 3. Les évènements moléculaires : récepteurs de surface et ligands. Cytokines chimiokines et leurs récepteurs

4 La coopération T – B l’effet haptène-porteur (Ovary et Benacerraf, 1963)
porteurs NIP OVA BSA BSA NIP OVA NIP BSA B cells BSA T cells Réponse Ac secondaire Intense À NIP-BSA

5 La coopération T-B Le modèle du pont Antigénique
NIP OVA BSA Recognition phase Production phase Activation phase : + proliferation + differentiation B cell BcR cooperation Ag Bridge model TcR T cell Antibody production

6 T-cells must be activated by Ag Presenting cells to cooperate with B cells (3 cells partnership)
Activation phase : + proliferation + differentiation Primed B cell BcR cooperation TcR Activ T cell APC cooperation

7 La Restriction allogénique : La présentation de l’Ag au TCR est restreinte par le MHC (Doherty et Zinkernagel, 1975) MHC classe II T cell TCR CD3 Cellule dendritique B cell

8 TcR ne peuvent reconnaître leurs epitopes qu’en association avec molecules MHC :La version moderne du pont antigénique Ag B cell BcR Primed B cell Endocytosis Ag digestion T epitopes Transfert on Class II Export to the membrane B epitopes Activ.T cell cooperation DC

9 La coopération cellules T- cellules B,
Un long ballet avec de nombreux partenaires 1. 50 années de coopération T – B : La question du pont antigènique 2. Les évènements cellulaires ; la réaction du centre germinatif. 3. Les évènements moléculaires : récepteurs de surface et ligands. Cytokines chimiokines et leurs récepteurs

10 T – B Cooperation : a cascade of synapses (#1 & 2)
Naive T cell Soluble Ag T cell Zone Day Day 1 Synapse 3 Synapse 1 Synapse 2 Activated DC Naive B cell Soluble Ag Cell bound Ag Primary follicle DC Secondary follicle Secondary follicle B CXCL13 B Th Th CXCR5 B B B Short lived plasma cells (No somatic hypermutation) Day 7

11 T et B se rencontrent :une question d’équilibres
De parfums B Ag Naive B cell CXCL13 CXCL13 CXCR5 CXCL13 B Th Activ B CXCR5 CCR7 CCL19 CCL21 Naive T cell CCL19 CCL21 CCL19 CCL21 CCL19 CCL21 T cell Zone CCR7 CCL19 CCL21

12 T – B Cooperation :The GC deadly ballroom
Bone marrow Long lived plasmocytes Germinal center Follicular dendritic cells Ag B B death + select. Centrocytes selection Memory B cells B B B T cell Zone Th B B Synapse 3 B Somatic hypermutations B B Light zone Clonal proliferation B B B B B Dark zone B B B B B Proliferation B B B B B B B B B B B B Day 14

13 T – B Cooperation : Old B cells remember with the help of old T cells
years Recall Ag Recall Ag mB mB mB mB mB mB mB mB mTh mB mTh mB mB Memory T helper B220- memory B B220+ memory B B220- CD136+ plasmocytes.

14 Diagram of T – B cooperation in B cell differentiation/activation
follicle Germinal center B1 or MZ B cells B2 cells Th cells Long lived plasmocytes Long term memory B 3 4.. Somatic Hypermutation & selection. 1 Ag contact Ag contact 2 Class Switch Recombin. DC Shorted lived plasmocytes 1 Memory Th Memory Th

15 La coopération cellules T- cellules B,
Un long ballet avec de nombreux partenaires 1. 50 années de coopération T – B : La question du pont antigènique 2. Les évènements cellulaires ; la réaction du centre germinatif. 3. Les évènements moléculaires

16 The molecular events : surface receptors & ligands
First signals : Ag recognition and initiation of the synapse Coactivation signals : crucial cosignals modulating signals Regulatory & inhibitory signals

17 First signal, 2d part : initiating the synapse
Class II signals Proliferation & differentiation Both early & late events CD3 ZAP70 Synergy with BCR & CD40 signals Associate with CD19 22 & CD40 (?) p56lck CD18 icam icam CD18

18 The synapse in T-B cooperation
Cell division & differentiation Early S meeting scanning Late synapse B 5 – 30 min. 12 – 24 hours B B B B B B Th Th Th Th Th Th Th

19 Ag recognitions during T-B cooperation a splited first signal
B cell BcR B cell Ag B cell Activ.T cell cooperation

20 The molecular events : surface receptors & ligands
First signals : Ag recognition and initiation of the synapse Coactivation signals : a) crucial signals b) modulating signals c) negative signals Depends mainly upon : Ig superfamily, partic. The CD28 family TNF/TNFR family members others : CD72 – CD100

21 The CD28/B7 families of coreceptors Inhibitors / activators
(Ig like superfamily) Receptor ligand CD28 CD86 CD80 CTLA-4 ICOS ICOS-L (B7RP1) PD1 PDL-1 PDL2 BTLA B7x TIM-3 ? Inhibitors / activators

22 The molecular events : surface receptors & ligands
First signals : Ag recognition and initiation of the synapse Coactivation signals : a) crucial signals CD28 – CD86/CD80 CD154 – CD4O ICOS – ICOSL CD100 – CD72

23 CD40 – CD154 The central pathway for T-B cooperation
Activated Tcell CD154 (CD4OL) inducible CD40 signal Synergy with the BCR signal B cell Increase adhesion And signal. mol. (CD80, 86, class II CD 95) IL-6, TNF, IL-10 & 12 LT, Ig, chemok. Clonal Proliferation Differentiation & Ab production germinal centers development Memory Bcells Isotype switching Humoral memory

24 The CD28 pathway is started by the CD40 pathway
5 6 CD86 2d signal CD3 TCR 3 1 1st signal CD4O CD40L 2

25 ICOS-/- mice have + no GC + a low Ig production,part. IgE.
Constitutive surf. Molecule Inducible surf. Molecule B7RP-1 Ag CD40 B7RP-1 CD86+CD80 CD28 ICOS Class II TcR Tc in GC CD40 CD154 CD28 CD40 CD154 1 2 3 CD86+CD80 ICOS TCR IL-4 & 13 Recept. IL-4 & 13 B cell prolif & differentiation

26 CD72 : stimulates B cell prolif., survival, MHC ClII expression
Potentializes MHC ClII and CD40 signals Required for diff. Of B-1 B cells, high affinity Ig responses to T dep. Ags CD100 CD72 TcR Class II Tc in GC CD40 CD154

27 The molecular events : surface receptors & ligands
First signals : Ag recognition and initiation of the synapse Coactivation signals : a) crucial signals b) modulating signals c) negative signals CD134 – 134L (OX40 - OX40L) CD137 – CD137 L (4-1BB – 4-1BBL) CD27 – CD70 BCMA - TACI

28 Prolonging and modulating B cell coactivation
1 : Once the CD40 and CD28 pathway fully works The CD134 (0X40) & 137 (4-BB1) pathways Help B cell proliferation deficient Ig switch (KO mice) IgM production normal GC OK CXCR5 CD134L CD134 Strong Coactivation signal Enhance B-cell prolif to anti µ, yet no effect Of humoral response In KO mice CD137L CD137 TCR CD28 CD4O CD154

29 Prolonging and modulating B cell coactivation
2 :Later on : Shaping the Immune response & setting long term memory TCR CD154 CD4O CD70 CD27 CD28 The CD27-CD70 pathway Required for development of: Memory cells plasma cells Terminal diff of B memory cells in plasma cells Late expression during T cell activ.

30 The BAFF / APRIL pathway
TNF like TNF-R

31 The molecular events : surface receptors & ligands
First signals : Ag recognition and initiation of the synapse Coactivation signals : a) crucial signals b) modulating signals c) negative signals CTLA-4 – CD80, CD86 CD30 – CD153 BTLA – B7H-RP CD95 – CD95L

32 Controling and terminating B cell proliferation/activation
1 : short term control within a synapse TCR CD28 CTLA4 within the CD28 pathway CD154 CD4O CD86 CD80 CTLA4 initial Few hours 1 – 2 days Time

33 PD1 – PD-L1, 2 pathway : an autoregulatory and Tolerogenic pathway
CTLA-4 CD80 TCR CD28 PD1 PD-L1, PD-L2 BCR PD1

34 - + BTLA – BTx : an attenuator pathway for T & B cells
BTLA & ICOS favour TH2 development in opposite way BTLA+++ ICOS- TH1 BTLA++ Naive T cell - BTLA++ BTLA- TH2 BTLA+- ICOS- + ICOS+++ T cell dependant in B cell help augmented in BTLA-/- mice (increasd B cell proliferation to BCR crosslink) BCR primed B cell Naive B cell B7x (ubiquitous) BTLA++ BTLA-

35 A model for a fine tuning of GC formation
by the CD28-B7 pathways Coyle & Gutierez-Ramos Nat Immunol 4, 647, 2003 T cell Zone Ag Activating signals Inhibitory signals Naive B cell STOP B CD80/86 CD28+ CTLA-4+ B B7RP-1 ICOS B Primed Th PDL1/2 PD-1 Naive T cell B7x B BTLA CD28+ Primed Th Primed Th STOP

36 Controling and terminating B cell proliferation/activation
2 :Later control : inhibiting isotype switch : the CD30/CD153 pathway 3 : Ultimate B cell extinction : Apoptosis via CD95 TCR CD154 CD4O CD153 CD30 CD28 Controling and terminating B cell proliferation/activation CD95 CD95L death inhibition

37 Long lived plasmocytes
CD40 ICOSL CD134L CD27 CD80 Germinal center Long lived plasmocytes follicle Long term memory B 3 B2 cells 4.. Somatic Hypermutation & selection. 1 Ag contact Ag contact 2 Class Switch Recombin. DC Shorted lived plasmocytes Th cells 1 Memory Th Memory Th

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39 Molecular pathways in T – B cell cooperation
functions B cell receptor T cell ligand adhesion activation Ag presentation , Enhance activation no Class II TCR, CD4 CD18/11a CD54, 18/11a ++++ Enhance activation Development of B1 cells Enhance activation IgG production CD72 CD100 CD40 CD154 CD134L CD134 CD137L CD137 CD30/153 CD27 CD170 CD30/153 CD95 CD95L

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