Cellular frustration: A new conceptual framework for understanding cell-mediated immune responses

Here we propose that frustration within dynamic interactions between cells can provide the basis for a functional immune system. Cellular frustration arises when cells in the immune system interact through exchanges of potentially conflicting and diverse signals. This results in dynamic changes in the configuration of cells that interact. If a response such as cellular activation, apoptosis or proliferation only takes place when two cells interact for a sufficiently long and characteristic time, then tolerance can be understood as the state in which no cells reach this stage and an immune response can result from a disruption of the frustrated state. Within this framework, high specificity in immune reactions is a result of a generalized kinetic proofreading mechanism that takes place at the intercellular level. An immune reaction could be directed against any cell, but this is still compatible with maintaining perfect specific tolerance against self.