T helper 17 cells and interleukin-17 immunity in type 1 diabetes: From pathophysiology to targeted immunotherapies

Abstract

Type 1 diabetes (T1D) is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells, which ultimately results in insulinopenia, hyperglycemia and lifelong need for exogenous insulin therapy. In the pathophysiological landscape of T1D, T helper 17 cells (Th17 cells) and their hallmark cytokine, interleukin (IL)-17, play pivotal roles from disease onset to disease progression. In this narrative mini-review, we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D, providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction. Furthermore, we summarized the main animal and clinical studies that investigated Th17- and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.

Keywords: Anti-interleukin-17 treatment; Interleukin-17; Regulatory T cells; T helper 1 cells; T helper 17 cells; Th17-targeted treatment; Type 1 diabetes.

Figure 1

Results of the literature search employed for the identification of studies on the role of T helper 17 cells and interleukin-17 in type 1 diabetes.

Figure 2

Natural history of type 1 diabetes and role of T helper 17 cells/interleukin-17 immunity in the pathophysiology of type 1 diabetes. Type 1 diabetes (T1D) stages are characterized by a progressive decline in beta-cell mass and function due to underlying autoimmune processes. A: Depicts the progressive decline in functional beta-cell mass throughout the sequential stages of T1D (stages of islet autoimmunity, dysglycemia and symptomatic disease); B: Illustrates the immune dysregulation observed in T1D, emphasizing the imbalance between pro-inflammatory T helper 17 (Th17) cells and regulatory T cells (Tregs). Th17 cells (involved in interleukin-17 production) promote beta-cell destruction, while Tregs (which physiologically maintain immune tolerance) are poorly represented and/or functionally impaired. This imbalance contributes to the immune-mediated destruction of insulin-producing beta cells and may be targeted by immunotherapies employed for the treatment of T1D. CD: Cluster of differentiation; T1D: Type 1 diabetes; IL-17: Interleukin-17; Th-17: T helper 17; FOXP3: Forkhead box P3; RORγt: Retinoic acid-related orphan receptor gamma t; Tregs: Regulatory T cells. Figure 2 was partly created with images adapted from Servier Medical Art licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0) (https://smart.servier.com/).