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.

Keywords: CD8 T cells; T cell proliferation; autoimmunity; inflammation; interferon gamma (IFNγ); type 1 daibetes mellitus.

FIGURE 1

The proinflammatory and regulatory functions of IFN-γ in T1D. The proinflammatory roles (left) include upregulation of MHC class I on the ß cell to increase recognition by CD8⁺ T cells, CXCL9 and CXCL10 production to recruit T cells to the islets and enhancing the proinflammatory function of macrophages. The regulatory roles of IFN-γ (right) include upregulation of the checkpoint molecule, PD-L1, in ß cells and upregulation of SOCS1 in CD8⁺ T cells to control signaling through common γ chain cytokines. Both of these limit T cell proliferation. JAK inhibitors can block both proinflammatory ß cell IFN-γ signaling and γc cytokine responses in T cells to limit ß cell destruction. The figure was made using Affinity Designer version 1.10.6.