Transcript Telesco0816 - Penn Engineering

Regulation of immunity through
T-cell competition for interleukin-2
Shannon Telesco
Advisor: Ravi Radhakrishnan, PhD
Regulation of the
immune system



T helper (Th) cells are a type of white blood cell that is part of
the body’s immune response. Th cells recognize foreign
antigens and activate additional immune cells to mount an
inflammatory reaction.
T regulatory (Treg) cells are a specialized subpopulation of T
cells that act to suppress activation of the immune system and
thereby maintain immune system homeostasis and tolerance to
self-antigens.
Th and Treg cells compete for a common growth factor called
interleukin-2 (IL-2). The outcome of this competition
determines whether the immune system will become activated
or suppressed.
Competition for IL-2



Treg are controlled by Th
cells via the level of available
IL-2.
Under tolerogenic
conditions, Th cells produce
low amounts of IL-2 in
response to self-antigen
(Ag) stimulation.
Under immunogenic
conditions, Th cells produce
high amounts of IL-2,
allowing activation of both
Th and Treg cells.
Scheffold, A., Huhn, J., & Hofer, T (2005). Regulation of CD4+CD25+ regulatory T cell activity:
it takes (IL-)two to tango. Eur. J. Immunol. 35:1336.
The IL-2 trafficking system
dRk
 kon Lk Rk  koff Ck  kt Rk  Vs  k synCk
dt
kon
koff
dCk
 k on Lk Rk  k off Ck  k e Ck
dt
dRi k
 k fe Lik Ri k  k reCik  k t Rk  k deg Ri k
dt
dLik  k fe Lik Ri k  k reCik

 k rec Lik
dt
Ve N A
dCik
 k fe Lik Ri k  k reCik  k deg Cik  k e Ck
dt
k=1 (Th cell) or k=2 (Treg cell)
krec
kdeg
Scaling the System


dR

 



d Ci
  L R C   (1  R)   C







  ( Li Ri  Ci)   Ci  C
dt
dt
d Ri





d Li
  (Ci Li Ri )   ( R  Ri )

dt
1 
 L R
C

1
dt
dC






  (Ci Li Ri )   Li
dt
Scaled Parameters:
k
 t
koff

k syn

k e k deg
k off
k t k off

ke
k e  k off


k
  re
k off
k feVs
k deg k off N AVe


k rec
k off
k deg
k off
 
Defining IL-2 parameters
Parameter
Definition
Value
kon
rate constant for ligand/receptor association at cell surface
1.38E9/(M*min)
koff
rate constant for ligand/receptor dissociation at cell surface
0.0138/min
kfe
rate constant for ligand/receptor association in endosome
1.1E8/(M*min)
kre
rate constant for ligand/receptor dissociation in endosome
0.1104/min
kt
rate constant for constitutive receptor endocytosis
0.007/min
kdeg
rate constant for lysosomal degradation of receptor
0.035/min
ke
rate constant for endocytosis of complexes
0.04/min
krec
rate constant for recycling of intracellular ligand to cell surface
0.15/min
Vs
rate of new receptor synthesis
11/min
Ve
endosomal volume
1E-14 L
NA
Avogadro’s number
6.02E23
Q
Rate of ligand secretion by Th cell
10-500/min
kmed
Rate of ligand degradation in extracellular space
0.02/min
H
Distance between Th and Treg (scaled by rcell)
5 μm
Ligand diffusion in
spherical coordinates

 L
2
2
r


2 L


r r
2
 
  L( r )  0
where
Solution:
 
L( r ) 


 1 sinh( r  )  2 cosh( r  )


r

r
Boundary conditions:
D
L
| r 1  Q  k on R1 L1  k off C1  k rec Li1
r
D
L
| r  H  k on R2 L2  k off C 2  k rec Li2
r
r k
  cell med
D
Results: Criteria for inhibition
Two criteria for successful inhibition of Th cell:
Q
Vs1  Vs2 <<1 (ligand must be limiting)
2
0
Th Receptors
1
10
10
3
10
1
10
0
-1
0
2
10
Q/(Vs1+Vs2)<1
Q/(Vs1+Vs2)<1
Q/(Vs1+Vs2)=1
Q/(Vs1+Vs2)=1
Q/(Vs1+Vs2)>1
Q/(Vs1+Vs2)>1
10
-1
10
3
0
10
10
10
10
Th Complexes
Th Complexes
1
4
10
2
10
10
4
3
10
Th Receptors
3
10
05
10
5
Time
15
10
Time
20
15
Vs2
>1
Vs1
and
10
20 0
2
10
Q/(Vs1+Vs2)<1
Q/(Vs1+Vs2)<1
Q/(Vs1+Vs2)=1
Q/(Vs1+Vs2)=1
Q/(Vs1+Vs2)>1
Q/(Vs1+Vs2)>1
1
10
0
10
05
510
Time
15
10
Time
20
15
20
Critical autocrine number

Critical Au is more difficult to achieve when Treg is ON.

Treg cell required to prevent Th cell activation in response to self-Ag.
300
300
250
250
100
1400
Treg ON
1400
Treg OFF
1200
1200
1000
1000
800
600
Rec for Th (#)
150
Rec for Th (#)
150
Treg ON
Treg OFF
800
600
100
Treg ON
Treg OFF
50
50
0
1600
200
C for Th (#)
C for Th (#)
200
1600
0
0
100
200
0
Q (1/min)
Treg ON
400
Treg OFF
400
200
200
0
100
300
2000
Q (1/min)
0
300
100
200
0
Q (1/min)
300
100
200
Q (1/min)
300
Parameter sensitivity:
isolated Th cell
Magnitude of Normalized Steady-State Sensitivities
1
C1 (state)
0.9
•Th cell secretes ligand
into an infinite domain
•Because ligand
depletion effects are
negligible, system is
insensitive to endosomal
parameters
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
kf
ke
kt1
kr
Vs1 kre
Parameters
krec
kfe
ksyn kdeg
Parameter sensitivity:
Th + Treg cells
Magnitude of Normalized Steady-State Sensitivities
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Because Vs2/Vs1 > 1, Th
cell is more sensitive to
Treg cell’s parameters
Th more sensitive to
Treg for all parameters
directly related to
number of receptors
Th more sensitive to
itself for all parameters
related to number of
complexes
1.2
C1 (state)
1
0.8
0.6
0.4
0.2
0
Kd2 kt2 Kd1 Vs2 ke1 ke2 kt1 Vs1 kc2 Ke2 kc1 Ke1 ks1 ks2 kg1 kg2
Parameters
Parameter sensitivity:
Th + Treg cells
Magnitude of Normalized Steady-State Sensitivities
•Because Vs2/Vs1 > 1, Treg is
more sensitive to its own
parameters
•Treg is relatively sensitive to
Kd1, but not to any of Th
parameters that directly relate
to receptor number
C2 (state)
1.2
1
0.8
0.6
0.4
0.2
0
kt2 Kd2 ke2 Vs2 Kd1 Vs1 kt1 ke1 Ke2 kc2 kc1 Ke1 ks1 ks2 kg1 kg2
Parameters
Phase plot: Th cell, low Q
For maximum values of Vs1 & Vs2, Th forms <50
complexes (insufficient for activation).
Th
12
200
250
180
10
160
140
8
150
Vs1 (1/min)
# SS complexes (Th)
200
100
120
6
100
80
4
50
60
40
2
0
15
10
5
0
Vs1 (1/min)
0
20
40
60
80
100
120
20
0
Vs2 (1/min)
0
20
40
60
Vs2 (1/min)
80
100
120
Phase plot: Treg cell, low Q
Both Th & Treg are mildly activated at low ligand
secretion rates.
Treg
12
250
10
8
150
Vs1 (1/min)
# SS complexes (Treg)
200
200
100
50
150
6
100
4
0
15
150
10
2
50
100
5
Vs1 (1/min)
50
0
0
0
Vs2 (1/min)
0
20
40
60
Vs2 (1/min)
80
100
120
Phase plot: Th cell, high Q
At high Q, neither cell inhibits the other
Th
20
500
18
450
350
16
250
14
200
12
Vs1 (1/min)
# SS complexes (Th)
300
150
100
400
350
300
10
250
8
200
50
6
150
0
15
150
100
100
10
5
Vs1 (1/min)
4
2
50
0
0
50
Vs2 (1/min)
0
0
20
40
60
Vs2 (1/min)
80
100
120
Phase plot: Treg cell, high Q
Both Th & Treg are fully activated at high Q
Treg
20
2500
3000
18
16
2000
14
2000
Vs1 (1/min)
# SS complexes (Treg)
2500
1500
1000
500
12
1500
10
8
1000
6
4
0
15
10
5
0
Vs1 (1/min)
0
20
40
60
Vs2 (1/min)
80
100
120
500
2
0
0
20
40
60
Vs2 (1/min)
80
100
120
Regulation of immunity
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Key feature of the immune
system is mutual regulation
of Th & Treg cells.
At low levels of ligand
production, corresponding
to stimulation by self-Ags,
neither cell is fully
activated.
At high levels of ligand
production, corresponding
to stimulation by foreign
Ags, both cells become
activated in a sequential
manner.
De la Rosa, M., Rutz, S., Dorninger, H., and Scheffold, A. (2004). Interleukin-2 is essential for
CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34:2480.
Food for thought
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Can additional immunological states be
identified as a function of the cell-cell
distance?
What are the effects of multiple Treg cells on
suppression of Th cell?
How is Th/Treg cell interaction affected by
mediation by an antigen-presenting cell
(APC)?
Acknowledgments
Ravi Radhakrishnan, PhD
Casim Sarkar, PhD
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