Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors?

Abstract

Low vitamin D status is associated with an increased risk of immune-mediated diseases like inflammatory bowel disease (IBD) in humans. Experimentally vitamin D status is a factor that shapes the immune response. Animals that are either vitamin D deficient or vitamin D receptor (VDR) deficient are prone to develop IBD. Conventional T cells develop normally in VDR knockout (KO) mice but over-produce IFN-γ and IL-17. Naturally occurring FoxP3+ regulatory T cells are present in normal numbers in VDR KO mice and function as well as wildtype T regs. Vitamin D and the VDR are required for the development and function of two regulatory populations of T cells that require non-classical MHC class 1 for development. The two vitamin D dependent cell types are the iNKT cells and CD4/CD8αα intraepithelial lymphocytes (IEL). Protective immune responses that depend on iNKT cells or CD8αα IEL are therefore impaired in the vitamin D or VDR deficient host and the mice are more susceptible to immune-mediated diseases in the gut.

Figure 1. The effects of 1,25(OH)₂D₃ on CD4⁺ T cells

CD4⁺ T cells are distinguished from one another based on combinations of cell surface markers and the cytokines they produce. 1,25(OH)₂D₃ (1,25D3) has been shown to inhibit proliferation of T cells, suppress Th17 and Th1 cytokine production, induce regulatory T cells, induce IL-4 production by Th2 cells and induce NKT cell functions. Together the effects of 1,25D3 are to suppress T cell responses that are pathogenic in immune mediated diseases driven by Th1 and Th17 cells and induce regulatory cells that suppress autoimmunity.

Figure 2. Vitamin D regulated control of iNKT cell and TCRαβCD8αα cell numbers

iNKT cells and TCRαβCD8αα cells develop in the thymus following rearrangement of the TCR and diverge from conventional T cells at the CD4/CD8 double positive (DP) stage. A) iNKT cells that express the TCR start out low for CD4 and CD8 (DP_dim), CD1d Tetramer+, and CD24+. Maturation of the iNKT cell precursor results in apoptosis of the CD24⁺ cells, downregulation of CD24 and proliferation of the precursors. Vitamin D deficiency results in more apoptosis and fewer of the early iNKT cells that are CD24⁻/Tetramer⁺. The iNKT cells go on to proliferate and through 3 maturation stages (S). S1 iNKT cells are CD44⁻, S2 iNKT cells are CD44⁺, and S3 iNKT cells are both CD44⁺ and NK1.1⁺. VDR KO iNKT cells are blocked at the S2 to S3 transition and therefore the iNKT cells from VDR KO mice fail to fully mature. B) TCRαβCD8αα cell precursors are triple positive (TP, express CD4/CD8αβ/CD8αα). The TP thymocytes rearrange the TCRαβ and downregulate all forms of CD4 and CD8 (double negative, DN). There are fewer of the TCRαβCD8αα precursors in the thymus of vitamin D deficient and VDR KO mice. The DN TCRαβ cells migrate to the gastrointestinal tract and IL-15 induces the proliferation and upregulation of CD8αα. VDR KO DN/TCRαβ express low levels of the IL-15 receptor and proliferate poorly and as a result there are fewer TCRαβCD8αα T cells in the small intestine of VDR KO mice.