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Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments
- Source :
- Proceedings of the National Academy of Sciences. 107:3058-3063
- Publication Year :
- 2010
- Publisher :
- Proceedings of the National Academy of Sciences, 2010.
-
Abstract
- Cytokines are pleiotropic and readily diffusible messenger molecules, raising the question of how their action can be confined to specific target cells. The T cell cytokine interleukin-2 (IL-2) is essential for the homeostasis of regulatory T (Treg) cells that suppress (auto)immunity and stimulates immune responses mediated by conventional T cells. We combined mathematical modeling and experiments to dissect the dynamics of the IL-2 signaling network that links the prototypical IL-2 producers, conventional T helper (Th) cells, and Treg cells. We show how the IL-2-induced upregulation of high-affinity IL-2 receptors (IL-2R) establishes a positive feedback loop of IL-2 signaling. This feedback mediates a digital switch for the proliferation of Th cells and functions as an analog amplifier for the IL-2 uptake capacity of Treg cells. Unlike other positive feedbacks in cell signaling that augment signal propagation, the IL-2/IL-2R loop enhances the capture of the signal molecule and its degradation. Thus Treg and Th cells can compete for IL-2 and restrict its range of action through efficient cellular uptake. Depending on activation status and spatial localization of the cells, IL-2 may be consumed exclusively by Treg or Th cells, or be shared between them. In particular, a Treg cell can deprive a stimulated Th cell of its IL-2, but only when the cells are located in close proximity, within a few tens of micrometers. The present findings explain how IL-2 can play two disctinct roles in immune regulation and point to a hitherto largely unexplored spatiotemporal complexity of cytokine signaling.
- Subjects :
- Interleukin 2
Cell signaling
medicine.medical_treatment
T cell
Biology
Models, Biological
T-Lymphocytes, Regulatory
Mice
Immune system
Downregulation and upregulation
medicine
Animals
Computer Simulation
IL-2 receptor
Cell Proliferation
Feedback, Physiological
Mice, Inbred BALB C
Multidisciplinary
Interleukin-2 Receptor alpha Subunit
T-Lymphocytes, Helper-Inducer
Biological Sciences
Flow Cytometry
Cell biology
Cytokine
medicine.anatomical_structure
Gene Expression Regulation
Interleukin-2
Signal transduction
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 107
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....0aa370dd49db9768dfab9a138f9d0913