The quantal theory of immunity

Smith, Kendall A.

doi:10.1038/sj.cr.7310003

Cited by 29 publications

(16 citation statements)

References 68 publications

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“…It has previously been proposed that a T cell stimulus must exceed a discrete threshold to trigger proliferation (1,30). The IL-2Rα switch found here provides a mechanistic basis for this activation threshold.…”

Section: Discussionmentioning

confidence: 85%

Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments

Busse

Rosa

Hobiger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

243

299

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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 highaffinity 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.bi-stability | cell-to-cell communication | cytokine networks | mathematical modeling | reaction-diffusion systems

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Section: Discussionmentioning

confidence: 85%

Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments

Busse

Rosa

Hobiger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

243

299

View full text Add to dashboard Cite

show abstract

“…To this end, we generated a computational model to compare the potential consequences of the observed binary and a hypothetical graded IL-2 secretion for the adaptive immune response. The model allowed us to simulate the outcome of these different scenarios taking into account quantitative spatial information in the spleen (Busse et al, 2010; Chapman et al, 1981; Lischke et al, 2012; Mueller and Germain, 2009; Sabatos et al, 2008; Smith, 2006). Our model confirmed that Treg cells become activated by IL-2 at lower antigen concentrations than Th cells and predicted that graded IL-2 secretion would result in activation of all T cells in a very narrow range of antigen stimulus, which is represented by a very steep slope of the activation curve of Th and Treg cells.…”

Section: Discussionmentioning

confidence: 99%

Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

Fuhrmann

Lischke

Groß

et al. 2016

eLife

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The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digital) and CD25 is graded expressed whereas at population level both parameters show graded expression correlating with the antigen amount. Combining in vivo data with a mathematical model we demonstrate that only this binary IL-2 expression ensures a wide linear antigen response range for Teff and Treg cells under real spatiotemporal conditions. Furthermore, at low antigen concentrations binary IL-2 expression safeguards by its spatial distribution selective STAT5 activation only of closely adjacent Treg cells regardless of their antigen specificity. These data show that the mode of IL-2 secretion is critical to tailor the adaptive immune response to the antigen amount.DOI: http://dx.doi.org/10.7554/eLife.20616.001

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“…We used flow cytometry to assess the capacity of the new molecule to bind to the CTLL-2 cells. This cell line expresses the highaffinity abg IL-2R just as the activated T cells do, with $5-10-fold excess of the free a-chain (20). For detection of His-tagged recombinant proteins bound to the cell surface, we used a PEconjugated anti-His-tag mAb.…”

Section: Mutein Productionmentioning

confidence: 99%

Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2

Carmenate

Pacios

Enamorado

et al. 2013

The Journal of Immunology

108

116

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IL-2 has been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy and severe toxicity. Currently, it is assumed that part of the limited efficacy is due to the IL-2–driven preferential expansion of regulatory T cells, which dampen the antitumor immunity. In this study, we characterize a human IL-2 mutant with higher antitumor efficacy and lower toxicity than wild type human IL-2 (wtIL-2). The mutant differs from wtIL-2 by four mutations at the interface with the α subunit of IL-2R. The IL-2 mutant induces in vitro proliferation of CD8+CD44hi and NK1.1 cells as efficiently as does wtIL-2, but it shows a reduced capacity to induce proliferation of CD4+Foxp3+ regulatory T cells. The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. In silico simulations, using a calibrated mathematical model, predict that the properties of IL-2 mutein are a consequence of the reduction, of at least two orders of magnitude, in its affinity for the α subunit of IL-2R (CD25). The human IL-2 mutant described in the present work could be a good candidate for improving cancer therapy based on IL-2.

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The quantal theory of immunity

Cited by 29 publications

References 68 publications

Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments

Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments

Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2

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