The incidence of inflammatory bowel disease (IBD) is highest for people that live in the Northern parts of the United States and Canada. Vitamin D status has been shown to change with season as a result of decreased sunlight exposure that produces vitamin D in the skin. In addition, the diet is a relatively poor source of vitamin D. Experimental IBD is more severe in vitamin D deficient mice and the active form of vitamin D (1,25(OH)2D3) suppresses the disease. We hypothesize that decreased outdoor activity and increased pollution and diets that lack adequate vitamin D have combined to create large fluctuations in vitamin D status in developed countries and especially in populations that experience winter. We propose that vitamin D exposure prenatally as well as postnatally alters immune function and as a result IBD. The vitamin D hypothesis proposes that vitamin D regulates the development and function of the immune system and that changes in vitamin D status especially prenatal as well as childhood alterations affect the development of the resultant immune response and the development of diseases like IBD. Our preliminary data show that the increased susceptibility of the vitamin D receptor (VDR) KO mice to experimental IBD is a result of altered T cell homing that results in few mucosal CD8aa regulatory T cells in the gut. We propose that CD8aa T cells require vitamin D and that even transient periods of low vitamin D status result in decreases in the CD8aa T cells of the intraepithelial lymphocytes (IEL). We hypothesize that vitamin D is required for the development of the mucosal CD8aa T cell receptor a[unreadable] IEL. The mechanisms involved might include an effect on gut T cell homing, development of CD8aa precursors in the thymus, and/or extrathymic signals that induce expression of CD8aa. The mechanisms by which vitamin D and the VDR regulate the CD8aa T cells will be determined. The data generated from these experiments is critical to the understanding of the effects of vitamin D on immunity and the potential use of high dose vitamin D as an alternative way to prevent or treat diseases like IBD. Public Health Relevance: There is at present a great deal of misinformation about vitamin D and vitamin D supplements as immune system modulators in the public forum. Identifying the cellular and molecular targets of vitamin D in the immune system is important so that rational decisions about the use of vitamin D supplements for healthy individuals as well as patients with autoimmune diseases like inflammatory bowel disease can be made.