Regulation of immunity through T-cell competition for interleukin-2

Shannon TelescoAdvisor: 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

ksynsktkoffkkonk CkVRkCkRLkdt

dR

kekoffkkonk CkCkRLk

dt

dC

kktkrekkfek RikRkCikRiLik

dt

dRideg

kekkrekkfek CkCikCikRiLik

dt

dCi deg

krecAe

krekkfek LikNV

CikRiLik

dt

dLi

kon

koff

kdegkrec

k=1 (Th cell) or k=2 (Treg cell)

Scaling the System

off

t

k

k

off

syn

k

k

offe

e

kk

k

off

re

k

k

offk

kdeg

offt

e

kk

kk degeAoff

sfe

VNkk

Vk

deg

off

rec

k

k

CRCRLtd

Rd )1(

CRL

td

Cd

1

1

)()(

RiRRiLiCitd

Rid

CCiCiRiLitd

Cid )(

LiRiLiCitd

Lid )(

Scaled Parameters:

Defining IL-2 parametersParameter 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

0)(2

2

2

rLr

L

rr

L

D

kr medcell2

r

r

r

rrL

)cosh()sinh()( 21

11111| LikCkLRkQr

LD recoffonr

2222| LikCkLRkr

LD recoffonHr

where

Boundary conditions:

Solution:

Results: Criteria for inhibition

Two criteria for successful inhibition of Th cell:

0 5 10 15 2010

-1

100

101

102

103

Time

Th C

om

ple

xes

0 5 10 15 2010

0

101

102

103

104

Time

Th R

ecepto

rs

Q/(Vs1+Vs2)<1

Q/(Vs1+Vs2)=1

Q/(Vs1+Vs2)>1

Q/(Vs1+Vs2)<1

Q/(Vs1+Vs2)=1Q/(Vs1+Vs2)>1

21 VsVs

Q

<<1 (ligand must be limiting) 1

2

Vs

Vs>1and

0 5 10 15 2010

-1

100

101

102

103

Time

Th C

om

ple

xes

0 5 10 15 2010

0

101

102

103

104

Time

Th R

ecepto

rs

Q/(Vs1+Vs2)<1

Q/(Vs1+Vs2)=1

Q/(Vs1+Vs2)>1

Q/(Vs1+Vs2)<1

Q/(Vs1+Vs2)=1Q/(Vs1+Vs2)>1

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.

0 100 200 3000

50

100

150

200

250

300

Q (1/min)

C f

or

Th (

#)

0 100 200 3000

200

400

600

800

1000

1200

1400

1600

Q (1/min)

Rec f

or

Th (

#)

Treg ON

Treg OFF

Treg ON

Treg OFF

0 100 200 3000

50

100

150

200

250

300

Q (1/min)

C f

or

Th (

#)

0 100 200 3000

200

400

600

800

1000

1200

1400

1600

Q (1/min)

Rec f

or

Th (

#)

Treg ON

Treg OFF

Treg ON

Treg OFF

Parameter sensitivity: isolated Th cell

kf ke kt1 kr Vs1 kre krec kfe ksyn kdeg0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Parameters

Magnitude of Normalized Steady-State Sensitivities

C1 (state)

•Th cell secretes ligand into an infinite domain

•Because ligand depletion effects are negligible, system is insensitive to endosomal parameters

Parameter sensitivity: Th + Treg cells

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

Kd2 kt2 Kd1 Vs2 ke1 ke2 kt1 Vs1 kc2 Ke2 kc1 Ke1 ks1 ks2 kg1 kg20

0.2

0.4

0.6

0.8

1

1.2

Parameters

Magnitude of Normalized Steady-State Sensitivities

C1 (state)

Parameter sensitivity: Th + Treg cells

kt2 Kd2 ke2 Vs2 Kd1 Vs1 kt1 ke1 Ke2 kc2 kc1 Ke1 ks1 ks2 kg1 kg20

0.2

0.4

0.6

0.8

1

1.2

Parameters

Magnitude of Normalized Steady-State Sensitivities

C2 (state)•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

Phase plot: Th cell, low QFor maximum values of Vs1 & Vs2, Th forms <50

complexes (insufficient for activation).

0 20 40 60 80 100 1200

2

4

6

8

10

12

Vs2 (1/min)

Th

Vs1

(1/

min

)

20

40

60

80

100

120

140

160

180

200

0 20 40 60 80 100 120

05

10150

50

100

150

200

250

Vs2 (1/min)Vs1 (1/min)

# S

S c

ompl

exes

(T

h)

Phase plot: Treg cell, low Q

Both Th & Treg are mildly activated at low ligand secretion rates.

0 20 40 60 80 100 1200

2

4

6

8

10

12

Vs2 (1/min)

Treg

Vs1

(1/

min

)

50

100

150

200

0

50

100

150

0

5

10

150

50

100

150

200

250

Vs2 (1/min)Vs1 (1/min)

# S

S c

ompl

exes

(T

reg)

Phase plot: Th cell, high Q

At high Q, neither cell inhibits the other

0 20 40 60 80 100 1200

2

4

6

8

10

12

14

16

18

20

Vs2 (1/min)

Th

Vs1

(1/

min

)

50

100

150

200

250

300

350

400

450

500

0

50

100

150

0

5

10

150

50

100

150

200

250

300

350

Vs2 (1/min)Vs1 (1/min)

# S

S c

ompl

exes

(T

h)

Phase plot: Treg cell, high Q

Both Th & Treg are fully activated at high Q

0 20 40 60 80 100 1200

2

4

6

8

10

12

14

16

18

20

Vs2 (1/min)

Treg

Vs1

(1/

min

)

500

1000

1500

2000

2500

0 20 40 60 80 100 120

05

10150

500

1000

1500

2000

2500

3000

Vs2 (1/min)Vs1 (1/min)

# S

S c

ompl

exes

(T

reg)

Regulation of immunity

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 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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