Presentation on theme: "B and T lymphocytes distinguish between self and foreign antigen receptor (BCR, TCR) Self antigens of the own body T cell Cell is not activated. No attack."— Presentation transcript:
B and T lymphocytes distinguish between self and foreign antigen receptor (BCR, TCR) Self antigens of the own body T cell Cell is not activated. No attack of own cells. strong binding foreign antigen weak binding Cell is activated. Foreign cells are attacked and killed. How does the cell distinguish self from foreign ? How does the receptor distinguish low from high affinity ligands ? DIE DREI EINLEITUNGSSLIDES MÜSSEN NOCH AUF EIN ODER ZWEI SLIDES ZUSAMMENGEFASST WERDEN. WIE, DAS HÄNGT DAVON AB, WAS VORHER GESAGT WIRD.
antigens immune response no response B cell antigen receptor BCR foreign: self: affinity Antigen receptors measure the receptor-ligand affinity independent of the concentration of the ligand. B and T lymphocytes distinguish between self and foreign
1.receptor-receptor affinity (pre-clustering) 2.Bivalent ligand binding 3.Intracellualr signalling network Model building Old model: New model:
Formation of a pre-clustered antigen receptor (BCR) Yang and Reth (2010), Nature Oligomeric organization of the BCR: Distribution of oligomeric BCR: Mathematical Model: + + internalization externalization KAKA KDKD Experimental Data: BN-PAGE 12 1: surface BCR 2: intracellular BCR WB: anti-BCR -> dynamic self-association of the receptors
Ligand-binding to pre-clustered antigen receptors (TCR) K1: ligand binding from solution K2: TCR-TCR interaction K3: multimeric ligand binding Crosslinked TCR pairs Log [pMHC-dimer], M K 2 = 10 (pre-clustered) K 2 = 0.1 (clustered on dimer binding) Bound TCRs 1/K 1 =1 M -> Receptor pre-clustering increases sensitivity in cooperation with AG Höfer, Viroquant
T cells can distinguish different affinity ligands -> T cells can distinguish high from low affinity ligands, largely independent of the ligand concentration. How is this done ? lig binding calcium influx Low affinity ligands do not induce Ca flux even at high TCR occupancy. TCR self antigens of the own body T cell is not activated. No immune response. high affinity foreign antigen low affinity T cell is activated. Immune response against foreign.
Different affinity ligand-binding to the TCR Ca 2+ High affinity ligands bind bivalently and stimulate the TCR. Low affinity ligands bind monovalently and do not stimulate the TCR. K 1 =0.1 M K 3 =10 K 1 =1 M K 3 =1 K 1 =10 M K 3 =0.1 high affinity intermediate affinity low affinity total amount of bound antigens bivalently bound antigens total binding dimeric binding -> Bivalent binding can explain ligand discrimination by T cells: in cooperation with AG Höfer, Viroquant, & SYBILLA EU FP7
Logical model of BCR signalling in cooperation with AG Haus, MaCS
Simulation of logical models will help to identify critical elements involved in certain output patterns. -> design of drugs to interfere with the network: treatment of auto-immune diseases and transplant rejections -> improve anti-tumoral immune responses Logical Model of BCR and TCR signalling ► Comparison of BCR signalling network and TCR signalling network: in cooperation with AG Schraven, MaCS