Vitamin D signaling in thymic development and longevity

Vitamin D has pleiotropic physiological roles including immune system regulation. Notably, there are links between vitamin D deficiency and risk of autoimmunity. Hormonal vitamin D binds to the vitamin D receptor (VDR) to exert its genomic effects. In immune cells, these include regulation of activation, inflammatory responses, and cytokine production. However, vitamin D supplementation is not efficacious in treatment of existing autoimmune disease. Conversely, vitamin D intake during childhood is associated with reduced risk of developing autoimmune type 1 diabetes. This supports a prophylactic role for vitamin D during this early developmental period wherein T cells undergo maturation in the thymus; importantly, highly self-reactive thymocytes undergo apoptosis due to interactions with specialized antigen presenting cells. Central to this process is the transcription factor autoimmune regulator (AIRE), which induces ectopic expression tissue restricted antigens in medullary thymic epithelial cells. Impaired AIRE function results in multiorgan autoimmunity in mice and humans. Vitamin D signaling regulates Aire expression and function in the mouse and, importantly, supports long-term thymic health by delaying aging-associated thymic involution. In humans, thymic aging is correlated with reduced naïve T cell output, impaired response to infection and cancer, and increased risk of autoimmunity. Collectively, existing data suggest that vitamin D sufficiency throughout the lifespan may be important for generating a self-tolerant T cell repertoire through its effects on AIRE and during aging by delaying aging-associated thymic involution. However, little is known about the links between thymic longevity and vitamin D status in humans, which represents a substantial knowledge gap.