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

1
Regulation of immunity through T-cell
competition for interleukin-2

• Shannon Telesco
• Advisor Ravi Radhakrishnan, PhD

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Regulation of the immune system

• T helper (Th) cells are a type of white blood
  cell that is part of the bodys 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.

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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 CD4CD25 regulatory T cell
activity it takes (IL-)two to tango. Eur. J.
Immunol. 351336.
4
The IL-2 trafficking system
kon
koff
krec
kdeg
k1 (Th cell) or k2 (Treg cell)
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Scaling the System
Scaled Parameters
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Defining IL-2 parameters
Parameter Definition Value
kon rate constant for ligand/receptor association at cell surface 1.38E9/(Mmin)
koff rate constant for ligand/receptor dissociation at cell surface 0.0138/min
kfe rate constant for ligand/receptor association in endosome 1.1E8/(Mmin)
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 Avogadros 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
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Ligand diffusion in spherical coordinates
where
Solution
Boundary conditions
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Results Criteria for inhibition

• Two criteria for successful inhibition of Th cell

ltlt1 (ligand must be limiting)
gt1
and
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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.

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Parameter sensitivity isolated Th cell

• Th cell secretes ligand into an infinite domain
• Because ligand depletion effects are negligible,
  system is insensitive to endosomal parameters

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Parameter sensitivity Th Treg cells

• Because Vs2/Vs1 gt 1, Th cell is more sensitive to
  Treg cells 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

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Parameter sensitivity Th Treg cells

• Because Vs2/Vs1 gt 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

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Phase plot Th cell, low Q

• For maximum values of Vs1 Vs2, Th forms lt50
  complexes (insufficient for activation).

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Phase plot Treg cell, low Q

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

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Phase plot Th cell, high Q

• At high Q, neither cell inhibits the other

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Phase plot Treg cell, high Q

• Both Th Treg are fully activated at high Q

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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 CD4CD25 regulatory T cell function. Eur.
J. Immunol. 342480.
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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)?

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Acknowledgments

• Ravi Radhakrishnan, PhD
• Casim Sarkar, PhD

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