Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments.
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 distinct roles in immune regulation and point to a hitherto largely unexplored spatiotemporal complexity of cytokine signaling.
Research Group Modeling of Biological Systems (B086), German Cancer Research Center, 69120 Heidelberg, Germany.
Dorothea
D
Busse
Maurus
M
de la Rosa
Kirstin
K
Hobiger
Kevin
K
Thurley
Michael
M
Flossdorf
Alexander
A
Scheffold
Thomas
T
Höfer
D000818:Animals; D049109:Cell Proliferation; D003198:Computer Simulation; D025461:Feedback, Physiological; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007376:Interleukin-2 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit