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

Abstract

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.

Keywords: cytokine; immunotherapy; type 1 diabetes; β‐cell destruction.

Figure 1

Cytokines involved in T1D. Cytokines produced by immune and pancreatic cells play diverse roles in T1D, which influences the development and progression of this disease. Cytokines such as IL‐10, TGF‐β, IL‐5, IL‐4, IL‐2, IL‐15, IL‐33 and IL‐35 can induce a regulatory phenotype in immune cells, which in turn release anti‐inflammatory cytokines such as IL‐10. In particular, IL‐7, released by regulatory DCs, is important for maintaining Tregs, which selectively express IL‐7Rα in T1D. Proinflammatory cytokines such as IL‐6, TNF‐α, IFN‐α, IL‐17 and IL‐21 amplify inflammation via proliferation and activation of diabetogenic immune cells, including Th1, Th17, CD8⁺ T cells and NK cells. However, because of the pleiotropic nature of cytokines, a given cytokine, such as IL‐2 or IL‐15, may trigger the activation of both diabetogenic and regulatory immune cells. In addition, β cells express high levels of cytokine receptors, such as IL‐1R, IL‐4R and IL‐22R, and exhibit increased sensitivity to cytokine‐induced apoptosis or regeneration. Thus, under in vivo conditions, the complexity of cytokine networks differentially contributes to the initiation and destruction phases of T1D.