Evolving immune circuits are generated by flexible, motile, and sequential immunological synapses

The immune system is made up of a diverse collection of cells, each of which has distinct sets of triggers that elicit unique and overlapping responses. It is correctly described as a ‘system’ because its overall properties (e.g. ‘tolerance’, ‘allergy’) emerge from multiple interactions of its components cells. To mobilize a response where needed, the majority of the cells of the system are obligatorily highly motile and so must communicate with one another over both time and space. Here, we discuss the flexibility of the primary immunological synapse (IS) with respect to motility. We then consider the primary IS as an initiating module that licenses ‘immunological circuits’: the latter consisting of two or more cell‐cell synaptic interactions. We discuss how two or three component immunological circuits interact might with one another in sequence and how the timing, stoichiometry, milieu, and duration of assembly of immunological circuits are likely to be key determinants in the emergent outcome and thus the system‐wide immune response. An evolving consideration of immunological circuits, with an emphasis on the cell‐cell modules that complement T‐antigen‐presenting cell interaction, provides a fundamental starting point for systems analysis of the immune response.