Effects of vitamin D supplementation on T cell activation and regulatory T cell development in Ldlr−/− mice
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BACKGROUND/OBJECTIVES: Atherosclerosis is a chronic inflammatory disease characterized by the buildup of low-density lipoprotein (LDL) within arterial walls, triggering inflammation and vascular constriction. Vitamin D has been shown to suppress T cell proliferation, reduce inflammatory responses, and promote the development of regulatory T cells (Tregs). However, its role in modulating T cell function in atherosclerotic models is not fully understood. This study examined the effects of vitamin D supplementation on T cell activation and Treg development in Ldlr−/− mice. MATERIALS/METHODS: C57BL/6J mice (CON) were fed a control diet (10% kcal fat), while B6.129S7-Ldlrtm1Her/J mice (ATH) were fed a Western diet (40% kcal fat + 0.15% w/w cholesterol). Both diets contained 1,000 or 10,000 IU vitamin D/kg diet (vDC or vDS, respectively) for 16 weeks. Purified T cells were stimulated using plate-bound anti-CD3ε/ soluble anti-CD28, then cultured for 48 h. Immune cell populations in the spleen, cytokine production by T cells, and the expression of key genes and proteins involved in Treg function, T cell receptor (TCR) signaling, and hypoxia were assessed. RESULTS: The expression of TCR signaling genes (Lck and Zap70) and the Treg transcription factor forkhead box P3 (Foxp3) were significantly higher in ATH compared to CON. Additionally, interleukin (IL)-10 levels were higher in ATH than in CON, while IL-17 and IL-2 levels did not show significant differences between the groups. Expression of hypoxia-inducible factor (Hif1a) was also higher in ATH compared to CON. Overall, vitamin D supplementation had a notable effect on Zap70 expression, which was lower in vDS compared to vDC. CONCLUSION: The higher Foxp3 expression and IL-10 production observed in the ATH suggest the activation of compensatory mechanisms to counteract inflammation. Enhanced TCR signaling in the ATH, likely associated with oxygen depletion due to heightened energy demand, may have contributed to the elevated Hif1a expression. The lower Zap70 expression in the vDS suggests that vitamin D supplementation suppresses T cell activation.
Abstract
BACKGROUND/OBJECTIVES: Atherosclerosis is a chronic inflammatory disease characterized by the buildup of low-density lipoprotein (LDL) within arterial walls, triggering inflammation and vascular constriction. Vitamin D has been shown to suppress T cell proliferation, reduce inflammatory responses, and promote the development of regulatory T cells (Tregs). However, its role in modulating T cell function in atherosclerotic models is not fully understood. This study examined the effects of vitamin D supplementation on T cell activation and Treg development in Ldlr−/− mice. MATERIALS/METHODS: C57BL/6J mice (CON) were fed a control diet (10% kcal fat), while B6.129S7-Ldlrtm1Her/J mice (ATH) were fed a Western diet (40% kcal fat + 0.15% w/w cholesterol). Both diets contained 1,000 or 10,000 IU vitamin D/kg diet (vDC or vDS, respectively) for 16 weeks. Purified T cells were stimulated using plate-bound anti-CD3ε/ soluble anti-CD28, then cultured for 48 h. Immune cell populations in the spleen, cytokine production by T cells, and the expression of key genes and proteins involved in Treg function, T cell receptor (TCR) signaling, and hypoxia were assessed. RESULTS: The expression of TCR signaling genes (Lck and Zap70) and the Treg transcription factor forkhead box P3 (Foxp3) were significantly higher in ATH compared to CON. Additionally, interleukin (IL)-10 levels were higher in ATH than in CON, while IL-17 and IL-2 levels did not show significant differences between the groups. Expression of hypoxia-inducible factor (Hif1a) was also higher in ATH compared to CON. Overall, vitamin D supplementation had a notable effect on Zap70 expression, which was lower in vDS compared to vDC. CONCLUSION: The higher Foxp3 expression and IL-10 production observed in the ATH suggest the activation of compensatory mechanisms to counteract inflammation. Enhanced TCR signaling in the ATH, likely associated with oxygen depletion due to heightened energy demand, may have contributed to the elevated Hif1a expression. The lower Zap70 expression in the vDS suggests that vitamin D supplementation suppresses T cell activation.