The concept that bone, kidney and intestine are the only sites of vitamin D action has recently required modification due to the discovery of high affinity cytosol receptors for vitamin D in nearly every vertebrate tissue examined. The demonstration of this receptor in these diverse tissues has been accompanied by the finding of significant biologic effects of vitamin D at physiologic concentrations. Vitamin D and its most biologically active metabolite, 1,25 dihydroxyvitamin-D3 (calcitriol), have been implicated as having significant effects on lymphocyte proliferation, immunoglobulin production and myeloid differentiation. Moreover, recent studies have demonstrated that, under certain conditions, macrophages can synthesize 1,25- dihydroxyvitamin D3 from its biologically inactive precursor, 25- hydroxyvitamin D3. Therefore, calcitriol appears to function not only as an endocrine hormone in maintaining calcium homeostasis, but also as a macrophage-derived product capable of modulating the immune response. We propose to examine the mechanisms by which calcitriol mediates its immunomodulatory activity on both a cellular and molecular level. Studies evaluating the effect of calcitriol on both T lymphocyte and monocyte differentiation and function will be performed. Thus, the examination of this novel aspect of vitamin D action has the potential to provide insights into not only the basic biology of the immune system and myeloid regulation but also the pathophysiology of a wide range of autoimmune and inflammatory disorders.