Type 1 diabetes (T1D) is an autoimmune disease that most commonly develops in early childhood. Studying T1D in humans is challenging because the destruction of insulin-producing β-cells in the pancreas occurs at a microscopic level and typically begins long before the first symptoms appear. Therefore, researchers use a mouse model of diabetes to study T1D. Although it differs from human T1D, this model helps understand the disease’s molecular mechanisms.
In T1D, β-cells are destroyed by CD8+ T-cells, which recognize them through the immune synapse. The immune synapse forms through interactions between CD8+ T-cells and pancreatic β-cells. The TCR receptor on the CD8+ T-cell surface binds to the primary histocompatibility complex class I (MHC-I) molecule on the β-cell. This molecule contains a peptide specific to β-cells. In T1D, the T-cell recognizes this peptide as foreign becomes activated, and attacks the β-cell. Thus, T1D could be prevented by blocking the cytotoxic function of CD8+ T-cells or suppressing their interaction with MHC-I molecules on β-cell surfaces.
Gamma interferon (IFN-γ) is a pro-inflammatory cytokine produced by immune cells that contributes to the inflammatory damage of pancreatic islets. Although IFN-γ was considered a potential therapeutic target for T1D, studies have shown that suppressing IFN-γ signals alone does not prevent β-cell destruction because IFN-γ can have both pathogenic and protective roles.
Researchers from the St. Vincent’s Institute in Australia have summarized the current knowledge on the role of IFN-γ in T1D and proposed using Janus kinase (JAK) inhibitors to prevent β-cell destruction.
Pro-inflammatory Role of IFN-γ in Type 1 Diabetes
IFN-γ plays a significant role in attracting T-cells, facilitating antigen presentation, and destroying β-cells, but its blockade alone is insufficient to prevent T1D.
Recruitment of CD8+ T-cells
IFN-γ helps recruit CD8+ T-cells to pancreatic islets by increasing CXCL10 chemokine expression on β-cells, chemokine receptor expression on CD8+ T-cells, and adhesion molecule expression (ICAM-1, MAdCAM-1, VCAM-1) on islet endothelial cells. Blocking CXCL10 reduces the risk of developing diabetes.
IFN-γ also promotes the recruitment and activation of inflammatory macrophages, which create a pro-inflammatory microenvironment that supports islet destruction.
Antigen Presentation
IFN-γ enhances MHC-I expression on β-cells, making them more recognizable to CD8+ T-cells. Experimental data indicate that reducing MHC-I levels or blocking IFN-γ signaling pathways decreases CD8+ T-cell proliferation, but diabetes still develops. Even the complete removal of interferon receptors does not stop the disease, as alternative antigen presentation by other antigen-presenting cells compensates.
Cell Death
IFN-γ, along with other cytokines (IL-1β, TNF-α), induces β-cell death by increasing iNOS enzyme production and activating intrinsic apoptotic mechanisms. However, blocking these pathways does not prevent diabetes, making IFN-γ blockade an ineffective target for T1D prevention.
Regulatory Role of IFN-γ in Type 1 Diabetes
T-cell Proliferation
IFN-γ acts as a brake on CD8+ T-cell proliferation. In mice lacking the IFNGR receptor, the number of islet-specific CD8+ T-cells increases due to heightened sensitivity to γc cytokines like IL-2, which is attributed to reduced SOCS1 expression—a protein regulated by IFN-γ that suppresses JAK-STAT signaling.
Enhanced γc cytokine signaling has also been linked to diabetes development in humans. Individuals with mutations in the STAT1 or STAT3 proteins involved in γc cytokine signaling are prone to T1D due to an increased number of effector CD8+ T-cells.
A similar effect is observed in mice lacking the PTPN2 enzyme, which restricts cytokine signaling. PTPN2 deficiency in T-cells enhances TCR sensitivity and cytokine responses, accelerating diabetes progression in mice.
Immune Checkpoints
IFN-γ stimulates PD-L1 (programmed death-ligand 1) expression on β-cells and antigen-presenting cells. PD-L1 interacts with the PD-1 receptor on activated T-cells, suppressing their activity and protecting β-cells from destruction. Blocking PD-L1 or PD-1 accelerates diabetes onset in mice by increasing CD8+ T-cell proliferation.
Thus, IFN-γ limits the CD8+ T-cell pool in autoimmune diabetes by regulating cytokine responses that promote T-cell survival and activating immune checkpoints to protect β-cells.
JAK Inhibitors
JAK inhibitors block the JAK-STAT signaling pathway and are used to treat autoimmune and inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, atopic dermatitis, and alopecia areata. Their mechanism of action involves inhibiting ATP binding, which is necessary for tyrosine kinase enzyme activation.
Types of JAK Inhibitors:
- First-generation (pan-JAK inhibitors): Target multiple JAK proteins.
- Second-generation: Selectively block specific JAK proteins, reducing side effects.
- Next-generation: Highly selective allosteric inhibitors.
JAK inhibitors are generally safe and well-tolerated. However, JAK1/JAK2 inhibitors may temporarily lower leukocyte and hemoglobin levels due to their impact on JAK2-dependent cytokines responsible for blood cell development. Other side effects include an increased risk of infections and shingles, as well as in high-risk individuals (e.g., smokers), cardiovascular diseases, and certain cancers. Selective JAK inhibitors reduce these risks by targeting specific cytokines.
JAK Inhibitors in Type 1 Diabetes
JAK inhibitors prevent β-cell death caused by pro-inflammatory cytokines and reduce MHC-I expression on β-cells in response to IFN-γ. Since the JAK-STAT pathway mediates signals from multiple cytokines, JAK inhibitors can target various cells involved in diabetes.
In diabetic mice, selective JAK1 inhibition blocks γc cytokine signaling in T-cells, reducing CD8+ T-cell proliferation and differentiation. This effect is more pronounced in CD8+ T-cells than in CD4+ T-cells, indicating a selective dependence of CD8+ T-cells on JAK-STAT cytokine signals.
JAK inhibitors also reduce CD8+ T-cell interactions with β-cells by decreasing MHC-I expression on β-cells. As a result, JAK inhibitors can prevent or even reverse diabetes in mice, including checkpoint inhibitor-induced diabetes (anti-PD-L1 therapy).
While JAK inhibitors mimic SOCS1 by inhibiting JAK-STAT interactions, their effects are broader, influencing inflammatory macrophages, antigen-presenting cells, and NK cells. Baricitinib—a JAK1/JAK2 inhibitor—is undergoing clinical trials for T1D (BANDIT study, NCT04774224).
Conclusion
IFN-γ contributes to T1D development by promoting T-cell migration to pancreatic islets and enhancing their ability to recognize and destroy β-cells. However, blocking IFN-γ alone in mice does not prevent diabetes progression. Although this approach has not been studied in humans, the data suggest it is likely ineffective.
IFN-γ drives inflammation and regulates CD8+ T-cell proliferation and PD-L1 expression, which limits β-cell destruction. Therefore, successful T1D treatment simultaneously suppresses IFN-γ’s inflammatory effects and limits T-cell proliferation.
JAK inhibitors achieve this by blocking the signaling of multiple cytokines, including interferons and γc cytokines. Their ability to act on both β-cells and immune cells distinguishes them from other approaches that target only the immune system. One such drug, baricitinib, is currently in clinical trials as a T1D treatment.
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Reference
Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis
