Interferon signaling is crucial for efficient functioning of the immune response. Its malfunction may have deleterious effects, and hence interferon signaling and response processes are tightly controlled. One might expect therefore, that nuclear localization of transcription factors activated by interferons is precisely regulated, and a specific concentration of one interferon variant leads to a very reproducible abundance of activated transcription factors in the same cell.
We find however, that nuclear abundance of tyrosine phosphorylated STAT1 protein, a transcription factor activated by interferons, exhibits substantial cell-to-cell variability when cells are exposed to a given doses of type I and type II interferon variant. The origin of this cell-to-cell heterogeneity is unknown. It might be, for instance, that the experimentally measured heterogeneity is a consequence of several tightly controlled processes that jointly determine a pecific nuclear abundance of a transcription factor. In that case observed heterogeneity is not mere randomness but a deterministic response to several stimuli, of which only one is experimentally controlled.
We have examined therefore if the cell cycle, one of the hierarchically superior cellular processes, controls response to IFNs and therefore contributes to cell-to-cell heterogeneity in a population of unsynchronized cells. We have found that the cell cycle has no effect on IFN responses i.e. subpopulations of cells in each of the four phases exhibit the same distribution of transcription factors abundances. This is non-obvious, if not surprising, observation because it means that despite substantial irreproducibility of IFN responses at the single cell level the signaling process is robust to the cell cycle. This finding suggests that the cell-to-cell heterogeneity may play a relevant biological role or have not been evolutionary eliminated for some important, and so-far rather obscure, reason.