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

foreignantigen

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

immuneresponse

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

aaa

P outcome

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PPK1RLK2K3 outcome1.

2. 3.

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

KA

KD

Experimental Data:

BN-PAGE1 2

1: surface BCR2: 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

Cro

sslin

ked

TC

R p

airs

Log [pMHC-dimer], M Log [pMHC-dimer], M

K2 = 10 (pre-clustered)K2 = 0.1 (clustered on dimer binding)

Bo

un

d T

CR

s

1/K1=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

foreignantigen

low affinity

T cell is activated.Immune response against foreign.

Different affinity ligand-binding to the TCR

Ca2+

Ca2+

Ca2+

Ca2+

High affinity ligands bind bivalently and stimulate the TCR.

Low affinity ligands bind monovalently and do not stimulate the TCR.

K1=0.1 M

K3=10

K1=1 M

K3=1

K1=10 M

K3=0.1

high affinity

intermediate affinity

low affinity

€

C =1Z

l N−dd

⎛ ⎝ ⎜

⎞ ⎠ ⎟ N −2dl −d

⎛

⎝ ⎜

⎞

⎠ ⎟

d=0

(minl,N−l)

∑l=1

N

∑ K1lK3

d

€

D=1Z

d N−dd

⎛ ⎝ ⎜

⎞ ⎠ ⎟ N −2dl −d

⎛

⎝ ⎜

⎞

⎠ ⎟

d=1

(minl,N−l)

∑l=1

N

∑ K1lK3

d

total amount of bound antigens

bivalently bound antigens

total bindingdimericbinding

-> 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

SHP-1

SLP-65

Iga/b

Syk

Lyn

HPK-1

Grb-2

PIP3

IKKa

Tak1

IKKb

CARMA Bcl10 Malt-1

TRAF2/6

Tab-2

IkBab

PKC

IKKg

Proteasome

RelA p50 c-Rel

Btk

DAGPLCg2

PI3K

CSK

SOSIP3

Ca2+Gsk3b

BCAPGab1

PTEN

PIP2

Akt

PDK

Ras RasGRP

Raf

MEK

ERK

Elk-1

MKP-1

TRAF3

NIK

RelB p52

p100

mIg CD22 CD72 PIR-B FcgRIIb BTLA CD40CD45CD19

PAG

pCD19

Vav

PKD

pCD22

SHIP

DOK3

RelA p50 RelAc-Rel RelB p52RelA RelA

PIP2

AND

feedback

activation

inhibition

(based on Boolean algebra)

CaM

Calcineurin

NFAT

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