Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response

Feinerman, Ofer; Jentsch, Garrit; Tkach, Karen; Coward, Jesse; Hathorn, Matthew M; Sneddon, Michael W.; Emonet, Thierry; Smith, Kendall A.; Altan‐Bonnet, Grégoire

doi:10.1038/msb.2010.90

Cited by 189 publications

(314 citation statements)

References 62 publications

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“…For example, membrane leakage and spiking threshold are set to make neurons respond only to a critical level of synaptic inputs [33]. Similar mechanisms have been observed at the cellular as well as cellular network scales [34][35][36][37]. Our results expose a mechanism by which reliable stimuli may overcome the activation threshold and be amplified even if they are carried by only a single member of the group.…”

Section: Discussionsupporting

confidence: 69%

Desert ants achieve reliable recruitment across noisy interactions

Razin

Eckmann

Feinerman

2013

J. R. Soc. Interface.

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We study how desert ants, Cataglyphis niger, a species that lacks pheromonebased recruitment mechanisms, inform each other about the presence of food. Our results are based on automated tracking that allows us to collect a large database of ant trajectories and interactions. We find that interactions affect an ant's speed within the nest. Fast ants tend to slow down, whereas slow ones increase their speed when encountering a faster ant. Faster ants tend to exit the nest more frequently than slower ones. So, if an ant gains enough speed through encounters with others, then she tends to leave the nest and look for food. On the other hand, we find that the probability for her to leave the nest depends only on her speed, but not on whether she had recently interacted with a recruiter that has found the food. This suggests a recruitment system in which ants communicate their state by very simple interactions. Based on this assumption, we estimate the information-theoretical channel capacity of the ants' pairwise interactions. We find that the response to the speed of an interacting nest-mate is very noisy. The question is then how random interactions with ants within the nest can be distinguished from those interactions with a recruiter who has found food. Our measurements and model suggest that this distinction does not depend on reliable communication but on behavioural differences between ants that have found the food and those that have not. Recruiters retain high speeds throughout the experiment, regardless of the ants they interact with; non-recruiters communicate with a limited number of nestmates and adjust their speed following these interactions. These simple rules lead to the formation of a bistable switch on the level of the group that allows the distinction between recruitment and random noise in the nest. A consequence of the mechanism we propose is a negative effect of ant density on exit rates and recruitment success. This is, indeed, confirmed by our measurements.

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Section: Discussionsupporting

confidence: 69%

Desert ants achieve reliable recruitment across noisy interactions

Razin

Eckmann

Feinerman

2013

J. R. Soc. Interface.

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“…For example, the activation of individual T cells does not occur homogeneously upon stimulation-even isogenic ones-but rather activate in a digital (on/off) manner, resulting from variations in transcriptional activity or gene accessibility (25,26), the numbers and dynamic expression of signaling receptors (e.g., CD8, IL-2R), and regulators of both positive and negative feedback loops (e.g., ERK, SHP-1, and RAS) (23,30,38,39). Expression of IL-2 and IFN-γ in human CD4 + T cells has also been shown to depend on the categorical translocation of the transcription factor NFATc2 (24).…”

Section: Discussionmentioning

confidence: 99%

Polyfunctional responses by human T cells result from sequential release of cytokines

Han¹,

Bagheri

Bradshaw

et al. 2011

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

295

298

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The release of cytokines by T cells defines a significant part of their functional activity in vivo, and their ability to produce multiple cytokines has been associated with beneficial immune responses. To date, time-integrated end-point measurements have obscured whether these polyfunctional states arise from the simultaneous or successive release of cytokines. Here, we used serial, timedependent, single-cell analysis of primary human T cells to resolve the temporal dynamics of cytokine secretion from individual cells after activation ex vivo. We show that multifunctional, Th1-skewed cytokine responses (IFN-γ, IL-2, TNFα) are initiated asynchronously, but the ensuing dynamic trajectories of these responses evolve programmatically in a sequential manner. That is, cells predominantly release one of these cytokines at a time rather than maintain active secretion of multiple cytokines simultaneously. Furthermore, these dynamic trajectories are strongly associated with the various states of cell differentiation suggesting that transient programmatic activities of many individual T cells contribute to sustained, population-level responses. The trajectories of responses by single cells may also provide unique, time-dependent signatures for immune monitoring that are less compromised by the timing and duration of integrated measures.microengraving | multifunctionality | dynamical systems | computational biology

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“…The efficacy of an immunotherapy depends upon its ability to effectively overcome immune evasion mechanisms and generate new antitumor responses and/or upregulate the existing responses. Feinerman et al 45 suggested a tug-of-war hypothesis, in which there is competition for IL-2 between Tregs and Teff cells. Although our study used the down-regulation of IL-2 as an indicator of Treg function, it is unclear whether IL-2 is the primary molecular target of suppression.…”

Section: Western Blot Analysismentioning

confidence: 99%

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Dou

Liu

et al. 2012

Cell Mol Immunol

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Lymphoma cells mobilize many mechanisms to evade the immune system. There is substantial evidence that CD4 1 CD25 1 regulatory T cells (Tregs) play a key role in the control of immune evasion. Tregs can transfer cyclic adenosine monophosphate (cAMP) to effector T cells, suggesting an association between Tregs' immune-evasion role and the intracellular cAMP pathway. In this study, we used A20 B-cell lymphoma mice as aggressive tumor models to investigate the mechanism of the depletion of Tregs by low-dose cyclophosphamide (CY, 20 mg/kg). The tumor-bearing mice had longer survival times and slower tumor growth rates following treatment with CY, but its effects were temporary. Along with the depletion of Tregs by low-dose CY treatment, the expression of interleukin-2 (IL-2) in T effector cells increased, and intracellular cAMP concentrations in immune cells decreased. Our study demonstrates the ability of low-dose CY to reverse Tregs-mediated immune evasion in a mouse model. The changes in intracellular cAMP concentrations correlated with the upregulation of effector T cells and the downregulation of Tregs, indicating the close association of cAMP analogs and low-dose CY in the immune therapy of B-cell lymphoma.

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Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response

Cited by 189 publications

References 62 publications

Desert ants achieve reliable recruitment across noisy interactions

Desert ants achieve reliable recruitment across noisy interactions

Polyfunctional responses by human T cells result from sequential release of cytokines

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

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