Gene regulatory networks in the immune system

•Gene regulatory networks (GRNs) reveal molecular logic of immune cell differentiation.•GRNs provide causal explanations for developmental and effector states of immune cells.•Immune cell GRNs use counter-repression, positive feedback, and feedforward motifs.•Mathematical modeling of GRNs predicts immune cell fate dynamics.•Assembly of complex GRNs is leading to discovery of many new regulatory components.

We describe examples of genomic control circuits that underlie developmental transitions and cellular activation states within the immune system. The architectures of simple gene regulatory networks (GRNs) are highlighted to emphasize conservation of regulatory motifs. The regulatory logic and the cell fate dynamics of each simple GRN, the latter revealed by mathematical and computational modeling, are elaborated. This framework is being expanded to enable the assembly and analysis of complex GRNs using genomic, computational, and high-throughput experimental methodologies. The paradigm will provide new insights into immune cell development and function, and into the pathophysiology of autoimmune and inflammatory disorders, as well as immune malignancies.