Scientists Discover How Two Immune Cell Types Team Up to Trigger Type 1 Diabetes

Scientists have identified a crucial partnership between two types of immune cells that drives the development of type 1 diabetes. The research shows that CD161+CD4+ T cells communicate with natural killer (NK) cells through a protein called interleukin-21 (IL-21), creating a destructive alliance that attacks the pancreas's insulin-producing beta cells.

How Do These Immune Cells Cause Type 1 Diabetes?

The study found that patients with newly diagnosed type 1 diabetes have an expanded population of highly active CD226+CD56dimCD16+ natural killer cells. These cells show enhanced ability to kill other cells, increased inflammation, and altered glucose metabolism compared to healthy individuals. What makes this discovery significant is that these aggressive NK cells actually decrease during remission phases of the disease, suggesting they play a direct role in disease progression.

Using single-cell ribonucleic acid (RNA) sequencing technology, researchers discovered that the frequency of CD226+ NK cells directly correlates with how quickly type 1 diabetes progresses. The more of these cells present, the faster patients lose their ability to produce insulin naturally.

What Triggers This Immune Cell Partnership?

The research revealed a specific communication pathway between immune cells that hadn't been fully understood before. CD161+CD4+ T cells release IL-21, which binds to receptors on NK cells and activates a cellular pathway called mechanistic target of rapamycin (mTOR) signaling. This process transforms normal NK cells into the aggressive CD226+ variety that infiltrates the pancreas and contributes to beta cell destruction.

The scientists tested this mechanism in female mice and found several ways to interrupt this harmful partnership:

• CD226 Blockade: Blocking the CD226 protein on NK cells reduced their activation and delayed diabetes onset
• IL-21 Receptor Inhibition: Using fusion proteins to block IL-21 receptors prevented NK cell activation and reduced pancreatic infiltration
• mTOR Pathway Disruption: Inhibiting the mTOR signaling pathway that IL-21 activates also protected against diabetes development

Could This Lead to New Treatments?

This discovery bridges a gap between adaptive immunity (T cells) and innate immunity (NK cells) in type 1 diabetes development, potentially opening new therapeutic avenues. The researchers used machine learning models to identify NK cell and CD4+ T cell subsets as predictors of beta cell functional decline, suggesting these immune cell populations could serve as biomarkers for disease monitoring.

The study's findings are particularly important because they show this immune cell crosstalk occurs not just during disease onset but also changes during remission periods. This suggests that targeting the IL-21-CD226+ NK cell axis could potentially be exploited in type 1 diabetes immunotherapy, offering hope for treatments that could prevent or slow the autoimmune destruction of insulin-producing cells.

The research involved analyzing blood samples from type 1 diabetes patients at different disease stages and comparing them with healthy controls, providing a comprehensive view of how these immune cell interactions change over time. The team also validated their findings using mouse models, demonstrating that interrupting this cellular communication pathway can protect against diabetes development.