Abstract
The cytokine IL-2 performs opposite functions supporting efficient immune responses and playing a key role in peripheral tolerance. Therefore, precise fine-tuning of IL-2 expression is crucial for adjusting the immune response. Combining transcription factor analysis at the single cell and the single nucleus level using flow cytometry with statistical analysis, we showed that physiological differences in the expression levels of c-Fos and NFATc2, but not of c-Jun and NF-κBp65, are limiting for the decision whether IL-2 is expressed in a strongly activated human memory T-helper (Th) cell. Variation in the expression of c-Fos leads to substantial diversity of IL-2 expression in ∼40% of the memory Th cells. The remaining cells exhibit an equally high c-Fos expression level, thereby ensuring robustness in IL-2 response within the population. These findings reveal how memory Th cells benefit from regulated variation in transcription factor expression to achieve a certain stability and variability of cytokine expression in a controlled manner.
Highlights
The precise fine-tuning of IL-2 expression is crucial for the immune system
Stable IL-2 Expression in Peripheral Memory Th Cell Population of Individual Donors—In view of the fact that IL-2 plays a crucial role for both immunity and peripheral tolerance, we assume that healthy individuals have a tailored and stable IL-2 production
The present study examined the impact of quantitative differences in the expression of the four main transcription factors NFATc2, NF-Bp65, c-Fos, and c-Jun (c-Fos/c-Jun ϭ AP-1) on IL-2 expression
Summary
The precise fine-tuning of IL-2 expression is crucial for the immune system. Results: Endogenous expression levels of c-Fos and NFATc2, but not of c-Jun and NF-Bp65, are limiting for IL-2 decision making. The remaining cells exhibit an high c-Fos expression level, thereby ensuring robustness in IL-2 response within the population These findings reveal how memory Th cells benefit from regulated variation in transcription factor expression to achieve a certain stability and variability of cytokine expression in a controlled manner. According to our findings, when human memory Th cells are subjected to strong stimulation the levels of the transcription factors NFATc2 and c-Fos, but not their activation and not c-Jun and NF-Bp65, correlate with IL-2 decision making at the single cell level. C-Fos Limits IL-2 Decision Making with Feinerman et al [20] our data show that the used quantitative single cell approach is useful for uncovering basic mechanisms during gene regulation, such as the existence and robustness of threshold levels, as well as the contribution of endogenous protein levels to cell response within a cell population
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