Diverse continuum of CD4+ T-cell states is determined by hierarchical additive integration of cytokine signals
Eizenberg-Magar, I., Rimer, J., Zaretsky, I. et al.
Understanding the logic by which cells respond to complex signal combinations is challenging. We used CD4+ T cells as a model system to study signal integration by systematically mapping their differentiation in response to a large number of cytokine combinations. We find that, in response to varied cytokine mixtures, cells coexpress lineage-specifying proteins at diverse levels, such that the cell population spans a continuum of intermediate states between canonical cell phenotypes. Mathematical modeling explains these results using hierarchical summation of cytokine inputs and correctly predicts population response to new input conditions. These findings suggest that complex cellular responses can be effectively described using relatively simple hierarchical summation rules, providing a framework for prediction of cellular responses to signal combinations.
Eizenberg-Magar, I., Rimer, J., Zaretsky, I. et al. "Diverse continuum of CD4+ T-cell states is determined by hierarchical additive integration of cytokine signals" Proceedings of the National Academy of Sciences of the United States of America (2017): E6447–56