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This article is based on research found in the following publication:

Mine, K., Nagafuchi, S., Akazawa, S. et al. TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes. Nat Commun15, 1337 (2024). https://doi.org/10.1038/s41467-024-45573-9

Type 1 diabetes (T1D) is an autoimmune disease where the body's own immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. With no cure currently available, patients require lifelong insulin therapy to manage their blood sugar levels. As the prevalence of T1D continues to rise globally, there is an urgent need to understand the underlying mechanisms driving this disease in order to develop effective preventive and therapeutic strategies.

Recent research has shed light on a potential key player in the pathogenesis of T1D: tyrosine kinase 2 (TYK2). TYK2 belongs to the Janus kinase (JAK) family of enzymes that regulate various cellular signaling pathways, including those involved in immune responses. While TYK2 has been implicated in other autoimmune disorders, its precise role in T1D remained poorly understood – until now.

In a groundbreaking study, researchers generated a novel mouse model by knocking out the Tyk2 gene in non-obese diabetic (NOD) mice, a widely used model for studying T1D. Their findings revealed that TYK2 plays a crucial role in driving the development of autoreactive CD8+ T cells, a type of immune cell responsible for destroying the body's own beta cells.

The researchers discovered that the absence of TYK2 impaired the function of these CD8+ T cells in two key ways. First, it disrupted the signaling of interleukin-12 (IL-12), a cytokine important for the activation and differentiation of CD8+ T cells into cytotoxic T lymphocytes (CTLs) capable of killing target cells. Second, it hindered the cross-priming of CTLs by CD8+ resident dendritic cells in the pancreatic lymph nodes, a process crucial for CTL activation against beta cell antigens.

Notably, the study found that TYK2-deficient CTLs exhibited reduced cytotoxicity, suggesting a weakened ability to destroy beta cells. Moreover, the inflammatory responses in beta cells, which typically increase with aging and contribute to T1D progression, were dampened in the absence of TYK2.

To further validate their findings, the researchers treated NOD mice with BMS-986165, a selective TYK2 inhibitor. Remarkably, this treatment inhibited the expansion of T-BET+ CTLs (a subset of CTLs implicated in T1D), reduced inflammation in beta cells, and delayed the onset of autoimmune T1D.

These exciting results highlight the diverse roles of TYK2 in driving the pathogenesis of T1D, from promoting the development of autoreactive CTLs to exacerbating inflammatory responses in beta cells. By elucidating the mechanisms through which TYK2 contributes to the disease process, this study paves the way for further exploration of TYK2 as a potential therapeutic target for T1D.

As research continues to unravel the complex interplay of genetic and environmental factors involved in T1D, targeting key players like TYK2 may hold promise for developing more effective treatments and preventive strategies. With a deeper understanding of the disease mechanisms, we move closer to a future where individuals with T1D can live without the constant burden of managing their condition.

ichorbio's anti-mouse IFN-β antibody (HDB-4A7) was used in this study.

ichorbio's anti-mouse IFN-α antibody (TIF-3C5) was used in this study.