B and T lymphocytes distinguish between self and foreign
description
Transcript of B and T lymphocytes distinguish between self and foreign
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
aaaa
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