TYK2 signaling promotes the development of autoreactive CD8 + cytotoxic T lymphocytes and type 1 diabetes.
Keiichiro MineSeiho NagafuchiSatoru AkazawaNorio AbiruHitoe MoriHironori KurisakiKazuya ShimodaYasunobu YoshikaiHirokazu TakahashiKeizo AnzaiPublished in: Nature communications (2024)
Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8 + T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8 + T-BET + cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8 + T cells and the CD8 + resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET + CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.
Keyphrases
- type diabetes
- tyrosine kinase
- lymph node
- induced apoptosis
- glycemic control
- dendritic cells
- cardiovascular disease
- cell cycle arrest
- oxidative stress
- epidermal growth factor receptor
- squamous cell carcinoma
- signaling pathway
- genome wide
- insulin resistance
- gene expression
- cell death
- neoadjuvant chemotherapy
- regulatory t cells
- drug induced
- early stage
- high fat diet induced
- smoking cessation
- bariatric surgery
- climate change
- innate immune