While vitamin D was discovered as the cure for nutritional rickets, it is active in numerous tissues unrelated to calcium homeostasis, in particular in the innate and adaptive arms of the immune system. Notably, vitamin D deficiency in infancy and early childhood is associated with increased risk of development of autoimmunity (e.g. type 1 diabetes). This can arise from impaired elimination of self-reactive T cells (central tolerance) during their maturation in the thymus. However, very little is known about the role of vitamin D signaling in thymic development and function. We are studying vitamin D signaling in mouse thymi, which are anatomically very similar to those of humans. Both the thymic stromal (epithelial) and hematopoietic (T cell) compartments express the vitamin D receptor (Vdr) and Cyp27b1, the enzyme catalyzing production of biologically active 1,25-dihydroxyvitamin D. Moreover, we found that the critical thymic transcription factor Aire (autoimmune regulator) is a cofactor of the Vdr. Remarkably, Cyp27b1-null mice display defective central tolerance, altered differentiation of the thymic stroma and accelerated thymic aging. In addition, aged Cyp27b1-null mice produce auto-antibodies and display evidence of immune cell invasion of pancreatic islets and glucose intolerance. Learning objectives: 1. To understand vitamin D metabolism and how and where 1,25-dihydroxyvitamin D is produced. 2. To obtain an overview of vitamin D signaling in the immune system and its relevance to human health. 3. To understand our current knowledge of how vitamin D signaling regulates the development and biology of the thymus and its relevance to autoimmunity.
John White obtained his B.Sc. and M.Sc. at Carleton University in Ottawa, and his Ph.D. in Biochemistry from Harvard. Postdoctoral work in Strasbourg France under the supervision of Professeur Pierre Chambon introduced him to the biochemistry of gene transcription and its regulation by estrogen. Dr. White was hired by the Physiology Department of McGill University in 1991, where he is now Professor and Chair. His laboratory has studied the mechanisms and physiological consequences of transcriptional regulation by nuclear receptors, concentrating since the early 2000’s on the vitamin D receptor (VDR). The lab’s work has focused on the non-classical actions of vitamin D. The White group has made major contributions towards understanding the potential role of vitamin D signaling in cancer prevention and in regulation of immune system function. Notably, the group performed the first large-scale gene expression profiling studies of 1,25D signaling, which led to the discovery that the VDR directly induces the expression of genes encoding antimicrobial peptides, the body’s natural antibiotics. This opened the field of study of vitamin D as an innate immune regulator. Subsequent work revealed that 1,25D stimulates the NOD2 -> DEFB4 innate immune pathway, whose compromised function is associated with increased risk of Crohn’s disease (CD). Recent studies have linked vitamin D signaling to events in the thymus that are fundamental for prevention of autoimmunity, and have shown that thymi undergo abnormal development and premature aging in the absence of vitamin D.