Stable IL-2 Decision Making by Endogenous c-Fos Amounts in Peripheral Memory T-helper Cells

Bendfeldt, Hanna; Benary, Manuela; Scheel, Tobias; Frischbutter, Stefan; Abajyan, Anna; Radbruch, Andreas; Herzel, Hanspeter; Baumgrass, Ria

doi:10.1074/jbc.m112.358853

Cited by 10 publications

(17 citation statements)

References 44 publications

(20 reference statements)

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“…Recently, we confirmed that U0126 does not inhibit the expression of NFATc2, c-Jun, and NF-κBp65 under the conditions used (Bendfeldt et al, 2012). U0126 inhibits de novo synthesis of c-Fos after T cell stimulation in a dose-dependent manner (Figure 7, upper part).…”

Section: Resultssupporting

confidence: 74%

IL-2 Expression in Activated Human Memory FOXP3+ Cells Critically Depends on the Cellular Levels of FOXP3 as Well as of Four Transcription Factors of T Cell Activation

et al. 2012

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The human CD4+FOXP3+ T cell population is heterogeneous and consists of various subpopulations which remain poorly defined. Anergy and suppression are two main functional characteristics of FOXP3+Treg cells. We used the anergic behavior of FOXP3+Treg cells for a better discrimination and characterization of such subpopulations. We compared IL-2-expressing with IL-2-non-expressing cells within the memory FOXP3+ T cell population. In contrast to IL-2-non-expressing FOXP3+ cells, IL-2-expressing FOXP3+ cells exhibit intermediate characteristics of Treg and Th cells concerning the Treg cell markers CD25, GITR, and Helios. Besides lower levels of FOXP3, they also have higher levels of the transcription factors NFATc2, c-Fos, NF-κBp65, and c-Jun. An approach combining flow cytometric measurements with statistical interpretation for quantitative transcription factor analysis suggests that the physiological expression levels not only of FOXP3 but also of NFATc2, c-Jun, c-Fos, and NF-κBp65 are limiting for the decision whether IL-2 is expressed or not in activated peripheral human memory FOXP3+ cells. These findings demonstrate that concomitant high levels of NFATc2, c-Jun, c-Fos, and NF-κBp65 lead in addition to potential IL-2 expression in those FOXP3+ cells with low levels of FOXP3. We hypothesize that not only the level of FOXP3 expression but also the amounts of the four transcription factors studied represent determining factors for the anergic phenotype of FOXP3+ Treg cells.

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Section: Resultssupporting

confidence: 74%

IL-2 Expression in Activated Human Memory FOXP3+ Cells Critically Depends on the Cellular Levels of FOXP3 as Well as of Four Transcription Factors of T Cell Activation

et al. 2012

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“…For intracellular staining of the transcription factors NFATc2 (Cy5-labeled own polyclonal antibodies (Bendfeldt et al, 2012), c-Fos (Alexa Fluor 488-labeled rabbit polyclonal IgG antibodies from Santa Cruz Biotechnology, RRID:AB_2231996), and Foxp3 (PE-Cy7-labeled antibody clone FJK-16s from eBioscience, RRID:AB_891554) the cells were stained with 1.34 µM Pacific Orange succinimidyl ester to exclude dead cells, fixed with Foxp3 fixation buffer (eBioscience), stained in Foxp3 permeabilization buffer (eBioscience), and analyzed using a LSR II flow cytometer (BD Biosciences). Data were analyzed with FlowJo software (Treestar, Ashland, OR).…”

Section: Methodsmentioning

confidence: 99%

“…There are a number of in vitro studies, some of them even combined with mathematical modeling, to dissect the dichotomic effect of IL-2 signaling in effector Th cells and Foxp3 + Treg cells (Benary et al, 2008; Bendfeldt et al, 2012; Busse et al, 2010; Feinerman et al, 2010; Tkach et al, 2014; Voisinne et al, 2015). Observations from various knock-out mice (e.g.…”

Section: Introductionmentioning

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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“…These findings are corroborated by a previous report showing that a specific MEK (MAP kinase/extracellular signal-regulated kinase) 1/2 inhibitor (upstream of c-Fos), U0126, inhibited de novo synthesis of c-Fos after T cell stimulation. As a result, the frequency of IL-2 producing cells was reduced within the human memory Th population, whereas the NFATc2 expression level remained unaffected (30). Based on our in vitro studies, we hypothesized that the suppression of alloreactive T cell responses by inhibiting cFos/AP-1 using T-5224 could contribute to preventing allogeneic rejection in PIT models.…”

Section: Discussionmentioning

confidence: 92%

The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation

Yoshida

Yamashita

Watanabe

et al. 2015

American Journal of Transplantation

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Stable IL-2 Decision Making by Endogenous c-Fos Amounts in Peripheral Memory T-helper Cells

Cited by 10 publications

References 44 publications

IL-2 Expression in Activated Human Memory FOXP3+ Cells Critically Depends on the Cellular Levels of FOXP3 as Well as of Four Transcription Factors of T Cell Activation

IL-2 Expression in Activated Human Memory FOXP3+ Cells Critically Depends on the Cellular Levels of FOXP3 as Well as of Four Transcription Factors of T Cell Activation

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

The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation

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