Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets

Cytokines play crucial roles in orchestrating complex multicellular interactions between pancreatic β cells and immune cells in the development of type 1 diabetes (T1D) and are thus potential immunotherapeutic targets for this disorder. Cytokines that can induce regulatory functions-for example, IL-10, TGF-β and IL-33-are thought to restore immune tolerance and prevent β-cell damage. By contrast, cytokines such as IL-6, IL-17, IL-21 and TNF, which promote the differentiation and function of diabetogenic immune cells, are thought to lead to T1D onset and progression. However, targeting these dysregulated cytokine networks does not always result in consistent effects because anti-inflammatory or proinflammatory functions of cytokines, responsible for β-cell destruction, are context dependent. In this review, we summarise the current knowledge on the involvement of well-known cytokines in both the initiation and destruction phases of T1D and discuss advances in recently discovered roles of cytokines. Additionally, we emphasise the complexity and implications of cytokine modulation therapy and discuss the ways in which this strategy has been translated into clinical trials.