Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis

Abstract

Type 1 diabetes is an autoimmune disease with onset from early childhood. The insulin-producing pancreatic beta cells are destroyed by CD8+ cytotoxic T cells. The disease is challenging to study mechanistically in humans because it is not possible to biopsy the pancreatic islets and the disease is most active prior to the time of clinical diagnosis. The NOD mouse model, with many similarities to, but also some significant differences from human diabetes, provides an opportunity, in a single in-bred genotype, to explore pathogenic mechanisms in molecular detail. The pleiotropic cytokine IFN-γ is believed to contribute to pathogenesis of type 1 diabetes. Evidence of IFN-γ signaling in the islets, including activation of the JAK-STAT pathway and upregulation of MHC class I, are hallmarks of the disease. IFN-γ has a proinflammatory role that is important for homing of autoreactive T cells into islets and direct recognition of beta cells by CD8+ T cells. We recently showed that IFN-γ also controls proliferation of autoreactive T cells. Therefore, inhibition of IFN-γ does not prevent type 1 diabetes and is unlikely to be a good therapeutic target. In this manuscript we review the contrasting roles of IFN-γ in driving inflammation and regulating the number of antigen specific CD8+ T cells in type 1 diabetes. We also discuss the potential to use JAK inhibitors as therapy for type 1 diabetes, to inhibit both cytokine-mediated inflammation and proliferation of T cells.

Exosomes isolated from IMMUNEPOTENT CRP, a hemoderivative, to accelerate diabetic wound healing

“…These results correlate with a study in which DFUs were treated with hyperbaric oxygen therapy, and only those treated that showed decreased TNF levels healed faster than the control ( Semadi, 2019 ). No statistical differences were observed in the IFN-γ expression at day 7, and it has been reported that IFN-γ expression does not influence the healing process nor the progression of type I diabetes ( De George et al, 2023 ). However, the IFN-γ KO mice demonstrated that defects in IFN-γ impaired wound healing; this could be correlated with decreased IFN-γ expression in mice treated with exosomes ( Kanno et al, 2019 ), being one of the treatments with a better clinical response.…”

The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner

“…Supporting an important role for CD69 + activated T cells in diabetes, CD69 expression has been found to be increased in T cells from insulin-stimulated whole blood from T1D patients compared to healthy controls ( 31 ) as well as in diabetic compared to nondiabetic T cells from NOD mice ( 32 ). IFN-γ also plays an important role in T1D pathogenesis by promoting homing of immune cells to pancreatic islets and facilitating β-cell antigen presentation ( 33 , 34 ). Lack of IFN-γ has been found to delay diabetes development in NOD mice ( 34 ).…”

Molecular mechanisms of Tangningtongluo Tablet in the treatment of diabetes based on network pharmacology and bioinformatics

“…Inhibiting IFNG can be a therapeutic strategy for T1DM since it plays a signi cant role in enhancing T cell homing to pancreatic islets and increasing the identi cation of β cells by CD8 + T cells [40]. The matrix metalloproteinase (MMPs) family includes MMP9 as one of its primary members.…”