Stable IL-2 decision making by endogenous c-Fos amounts in peripheral memory T-helper cells

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.