Cytokine multimerization: when more is more and sometimes less.

Cytokines are essential mediators of immune functions and regulate many other biological processes, ranging from fetal development to ageing. Dysregulation of cytokine responses can substantially increase the risk of disease and so their activity requires tight control. The formation of cytokine homodimers, heterodimers and multimers has evolved as a versatile mechanism to regulate cytokine biology, in which multimerization can enable or attenuate their activity, diversify signalling outcomes and drive signalling bias. Here, we discuss the structure-function implications of cytokine multimerization for type I cytokines (for example, the IL-6 and IL-12 cytokine families), type II cytokines (for example, the IL-10 and interferon families), cytokines that signal through immunoglobulin-family receptors (for example, the IL-1 and M-CSF families) and also for the IL-17, TNF and TGFβ cytokine families. We highlight the influence of multimerization on cytokine activity and receptor engagement, as well as the relevance of cytokine multimerization for disease development and the resulting therapeutic opportunities.