Probing Selenium-Deficient Chicken Spleen Th1/Th17 Differentiation Based on Selenoprotein W Targeting of PKM2/HIF1α

Abstract

Selenium regulates the differentiation and function of immune cells mainly through selenoproteins. Selenoprotein W (SelW) has been shown to mitigate inflammatory bowel disease in mice by modulating the differentiation of helper T (CD4⁺ T) cell. Previous studies by our team have underscored SelW’s critical role in safeguarding chicken spleens and splenic lymphocytes against inflammatory injury. However, research examining SelW’s involvement in regulating CD4⁺ T cell differentiation in avian spleens remains scarce. Therefore, the selenium-deficient chicken model was constructed in this study. It was found that the spleen of selenium-deficient chickens showed significant inflammatory damage, accompanied by decreased SelW expression, diminished antioxidant capacity, heightened glycolysis, and an elevated count of Th1/Th17 cells. To elucidate the specific mechanism of SelW regulating Th1/Th17 cell differentiation, this study used molecular docking technology, fluorescence colocalization, and co-immunoprecipitation and initially confirmed the targeting relationship between SelW and pyruvate kinase M2 (PKM2). Subsequently, an in vitro model of SelW overexpression, knockdown, and TEPP-46 (PKM2 tetramer activator) cotreatment of chicken primary splenic lymphocytes was replicated. Our findings revealed that selenium deficiency triggers oxidative stress and promotes PKM2 nuclear translocation via SelW downregulation, which stabilizes HIF1α transcription in the nucleus, enhancing glycolysis and skewing chicken splenic CD4⁺ T cells toward the Th1/Th17 phenotype. Our study, for the first time, demonstrates the existence of an interaction between SelW and PKM2 in poultry, emphasizing SelW’s paramount significance in CD4⁺ T cell differentiation, providing fresh perspectives on the contributions of selenoproteins to T cell biology and immune processes.