B-cell peripheral tolerance: think dynamics beyond affinity.

Maintaining B-cell tolerance - the elimination of self-reactive B-cells - is literally a life-long challenge because the B-cell receptor mutates to generate millions of new variants during each immune response in the germinal center (GC) of lymph nodes. B-cell tolerance therefore rests on local mechanisms within GCs, i.e., in the periphery, whereas classical T-cell tolerance mechanisms operate in the thymus (central tolerance) when T-cell diversity is generated during immune development. While T-cell tolerance has been shown to be mediated by kinetic proofreading mechanisms that are capable of distinguishing small affinity differences, we argue here that B-cell tolerance mechanisms in the GC operate at different timescales covering intra- and, inter-cellular signaling in the light zone, and iterative light-dark-zone cycling, where the temporal relationship between BCR and CD40 signaling are key to determining whether a B-cell is positively or negatively selected. This review summarizes how recent research points to a new conceptual paradigm for B-cell tolerance that must involve the analysis of intracellular and intercellular network dynamics. We show how multi-scale dynamical systems modeling will be key to elucidate B-cell selection mechanisms and enable a predictive understanding of how autoimmune pathologies arise.