Un double systme cellulaire et molculaire de reconnaissance

Un double système, cellulaire et moléculaire de reconnaissance de l’antigène thymus Bourse de Fabricius Ou moelle osseuse CD 3 Organe de différenciation Cellule souche T cell TCR Bc. R = immunoglobulines Récepteurs clonaux Peptide issu de l’antigène B cell MHC Antigène entier Antigène (protéine bactérienne)

Pour fabriquer des quantités optimales d’Ac affins, Les cellules B doivent avoir coopérer directement Avec les cellules T Cellule B 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

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

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

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

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

La Restriction allogénique : La présentation de l’Ag au TCR est restreinte par le MHC (Doherty et Zinkernagel, 1975) MHC classe II TCR T cell CD 3 Cellule dendritique B cell

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

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

Soluble Ag T – B Cooperation : a cascade of synapses (#1 & 2) Synapse 1 Synapse 3 Synapse 2 DC Secondary follicle Primary follicle Soluble Ag Activated DC Naive B cell Cell bound Ag CXCL 13 CXCR 5 Th B B B Naive T cell B Short lived plasma cells (No somatic hypermutation) Day 0 T cell Zone Day 1 Day 7

T et B se rencontrent : une question d’équilibres De parfums Ag B CXCL 13 Naive B cell CXCL 13 CXCR 5 CCR 7 Th Activ B CCR 7 CCL 19 CCL 21 Naive T cell CCL 19 CCL 21 B CXCR 5 CCL 19 CCL 21 CCL 19 T cell Zone

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

T – B Cooperation : Old B cells remember with the help of old T cells years Recall Ag m. B m. Th Memory T helper m. B m. Th m. B B 220 - memory B B 220+ memory B B 220 - CD 136+ plasmocytes.

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

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

The molecular events : surface receptors & ligands 1. First signals : Ag recognition and initiation of the synapse 2. Coactivation signals : crucial cosignals modulating signals Regulatory & inhibitory signals

First signal, 2 d part : initiating the synapse Class II signals Proliferation & differentiation Both early & late event CD 3 Synergy with BCR & CD 40 signals Associate with CD 19 22 & CD 40 (? ) ZAP 70 p 56 lck CD 18 icam CD 18

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

Ag recognitions during T-B cooperation a splited first signal Bc. R B cell Ag B cell cooperation Activ. T cell

The molecular events : surface receptors & ligands 1. First signals : Ag recognition and initiation of the synapse 2. Coactivation signals : a) crucial signals b) modulating signals c) negative signals Depends mainly upon : • Ig superfamily, partic. The CD 28 family • TNF/TNFR family members • others : CD 72 – CD 100

The CD 28/B 7 families of coreceptors (Ig like superfamily) Receptor ligand CD 28 CD 86 CTLA-4 CD 80 ICOS-L (B 7 RP 1) PD 1 PDL-1 PDL 2 BTLA B 7 x TIM-3 ? Inhibitors / activators

The molecular events : surface receptors & ligands 1. First signals : Ag recognition and initiation of the synapse 1. Coactivation signals : • a) crucial signals CD 28 – CD 86/CD 80 • CD 154 – CD 4 O • ICOS – ICOSL • CD 100 – CD 72

CD 40 – CD 154 The central pathway for T-B cooperation Activated Tcell CD 154 (CD 4 OL) inducible CD 40 signal Synergy with the BCR signal B cell Increase adhesion And signal. mol. (CD 80, 86, class II CD 95) IL-6, TNF, IL-10 & 12 LT, Ig, chemok. Clonal Proliferation Differentiation & Ab production Isotype switching germinal centers development Memory Bcells Humoral memory

The CD 28 pathway is started by the CD 40 pathway 4 CD 86 5 CD 28 6 2 d signal CD 3 TCR 3 1 CD 4 O 2 CD 40 L 1 st signal

ICOS-/- mice have + no GC + a low Ig production, part. Ig. E. Constitutive surf. Molecule Inducible surf. Molecule B 7 RP-1 ICOS Ag CD 40 CD 86+CD 80 Class II CD 28 Tc. R Tc in GC ICOS CD 86+CD 80 CD 28 CD 40 CD 154 3 TCR 2 1 IL-4 & 13 Recept. CD 40 CD 154 IL-4 & 13 B cell prolif & differentiation

CD 72 : stimulates B cell prolif. , survival, MHC Cl. II expression Potentializes MHC Cl. II and CD 40 signals Required for diff. Of B-1 B cells, high affinity Ig responses to T dep. Ags CD 72 Class II CD 40 CD 100 Tc. R Tc in GC CD 154

The molecular events : surface receptors & ligands 1. First signals : Ag recognition and initiation of the synapse 2. Coactivation signals : a) crucial signals b) modulating signals c) negative signals • CD 134 – 134 L (OX 40 - OX 40 L) • CD 137 – CD 137 L (4 -1 BB – 4 -1 BBL) • CD 27 – CD 70 • BCMA - TACI

Prolonging and modulating B cell coactivation 1 : Once the CD 40 and CD 28 pathway fully works The CD 134 (0 X 40) & 137 (4 -BB 1) pathways Help B cell proliferation deficient Ig switch (KO mice) Ig. M production normal GC OK CD 134 L Enhance B-cell prolif to anti µ, yet no effect Of humoral response In KO mice CD 137 L CXCR 5 CD 134 Strong Coactivation signal CD 137 TCR CD 28 CD 4 O CD 154

Prolonging and modulating B cell coactivation 2 : Later on : Shaping the Immune response & setting long term memory The CD 27 -CD 70 pathway Required for development of: Memory cells plasma cells CD 27 CD 70 Late expression during T cell activ. Terminal diff of B memory cells in plasma cells TCR CD 28 CD 4 O CD 154

The BAFF / APRIL pathway TNF like TNF-R

The molecular events : surface receptors & ligands 1. First signals : Ag recognition and initiation of the synapse 2. Coactivation signals : • • a) crucial signals b) modulating signals c) negative signals CTLA-4 – CD 80, CD 86 CD 30 – CD 153 BTLA – B 7 H-RP CD 95 – CD 95 L

Controling and terminating B cell proliferation/activation 1 : short term control within a synapse CTLA 4 within the CD 28 pathway 1 – 2 days CD 80 CTLA 4 Few hours CD 28 CD 86 initial Time TCR CD 4 O CD 154

PD 1 – PD-L 1, 2 pathway : an autoregulatory and Tolerogenic pathway CTLA-4 CD 80 TCR CD 28 PD 1 BCR PD 1 PD-L 1, PD-L 2

BTLA – BTx : an attenuator pathway for T & B cells BTLA & ICOS favour TH 2 development in opposite way Naive T cell BTLAICOS- BTLA+++ ICOS- TH 1 BTLA+- TH 2 ICOS+++ - + T cell dependant in B cell help augmented in BTLA-/- mice (increasd B cell proliferation to BCR crosslink) Naive B cell BTLA- BCR primed B cell BTLA++ B 7 x (ubiquitous)

A model for a fine tuning of GC formation by the CD 28 -B 7 pathways Coyle & Gutierez-Ramos Nat Immunol 4, 647, 2003 T cell Zone Ag Activating signals Inhibitory signals Naive B cell STOP CD 28+ CD 80/86 CD 28+ CTLA-4+ B 7 RP-1 ICOS PDL 1/2 PD-1 Primed B 7 x Th BTLA Naive T cell STOP Primed Th B B

Controling and terminating B cell proliferation/activation 2 : Later control : inhibiting isotype switch : the CD 30/CD 153 pathway 3 : Ultimate B cell extinction : Apoptosis via CD 95 death CD 95 inhibition CD 30 CD 95 L CD 153 TCR CD 28 CD 4 O CD 154

CD 40 ICOSL CD 134 L CD 80 CD 27 Germinal center Long lived plasmocytes follicle B 2 cells 3 1 DC Ag contact 2 Shorted lived plasmocytes Th cells 1 Memory Th Class Switch Recombin. Long term memory B 4. . Ag contact Memory Th Somatic Hypermutation & selection.

Molecular pathways in T – B cell cooperation pathways B cell receptor functions T cell ligand adhesion Class II TCR, CD 4 no activation Ag presentation , Enhance activation CD 18/11 a CD 54, 18/11 a ++++ Enhance activation CD 72 CD 100 CD 40 CD 154 CD 134 L CD 134 CD 137 L CD 137 CD 30/153 CD 27 CD 170 CD 30/153 CD 95 L Development of B 1 cells Enhance activation Ig. G production