Cantorna, M.T., M. Tang, and N. Froelich

The interest in vitamin D as an immune regulator began with the identification of vitamin D receptors (VDR) in cells of the immune system. Early studies showed that adding 1,25(OH)₂D (1,25D) to human T cells inhibited proliferation and reduced IL-2 and IFN-γ production, leading to the initial characterization of vitamin D as an immunosuppressive agent. However, evidence of vitamin D’s beneficial effects in host immunity against infections suggests an immunoregulatory rather than a suppressive role. The identification of immune cells that produce the enzyme that makes 1,25D (CYP27B1) has expanded our understanding of the regulatory role of vitamin D on immunity. 1,25D has been shown to suppress the production of several inflammatory cytokines in animal models and multiple disease contexts. In vivo, 1,25D treatments were shown to protect the colon from colitis development. 1,25D switched off Ifn-g production from Th1 cells and upregulated Il-10 production. The induction of Il-10 secreting regulatory cells by 1,25D was associated with reduced graft versus host disease, and less colitis in mice. The data suggests that vitamin D tips the immune axis from a Th1/Th17 reponse to a Th2/Treg response. Knocking out the VDR in mice results in high amounts of Tnf-a, Il-6, Il-1b, Il-12 and Ifn-g. Vitamin D deficient (D-) animals had more inflammation in the lung and colon than vitamin D sufficient (D+) animals. Moreover, treating D+ mice with supplemental vitamin D (D++) reduced Ifn-g and Tnf-a in the serum, brain and spleen, which was associated with protection from cerebral malaria. A recent study in SARS-CoV-2 patients with pneumonia that were treated high-dose vitamin D resultd in significantly shorter intensive care unit stays and significantly reduced amounts of IL-6, IL-17, and IL-1b in the plasma as compared to non treated patients. Only upon activation do immune cells produce CYP27B1 and this activation also upregulates the VDR. Our current model is that the effects of vitamin D on the immune system are delayed for several days until activation induces VDR and local 1,25D production that resolves inflammation and returns the immune system to homeostasis. Additional research into the mechanisms that control VDR and CYP27B1 in different immune cells and different tissues/disease models are needed to further elaborate on our understanding of why immune cells express the VDR.