Accumulating evidence indicates that clinically relevant vitamin D deficiency may be widespread throughout the human population (1). Insofar as exposure to sunshine provides much more vitamin D than can be obtained from dietary sources (1), this deficiency follows from the relatively recent transition in employment practices from hunting, gathering, and farming to the indoor activities characteristic of industrialized economies. The racial disparity in vitamin D status that is seen in the United States (2) along with the seasonal fluctuation of vitamin D levels measured in the United Kingdom (3) and elsewhere (4) highlights the contribution made by sunlight to vitamin D status.A large body of epidemiological and animal data suggests that vitamin D deficiency promotes autoinflammatory disease. The incidence of several human autoimmune diseases has been reported to correlate with increased geographical latitude, low vitamin D intake, and low vitamin D status (1). Systemically administered 1␣,25-dihydroxyvitamin D 3 (1,25-D 3 ), 2 the active form of vitamin D, protects mice against many experimental forms of autoimmune disease (5-9), and deficiency in the vitamin D receptor (VDR) aggravates inflammatory bowel disease in the CD45RB transfer and IL-10-null models (10). Topically applied vitamin D analogs are effective against human psoriasis (1), and a recent report suggests that VDR is a "master regulator" of mouse skin inflammation (11).The contributions made by CD4 T cells to the pathogenesis of many autoimmune diseases were historically ascribed to the activity of the Th1 subset. These cells express IFN-␥ and develop from naïve precursors by activation in the presence of IL-12 and by induction or activation of the transcription factors T-bet, STAT1 and STAT4 (12). More recently, a third effector T cell subset, Th17, has been linked to immunopathology in some forms of autoimmunity previously thought to be Th1-mediated (12). Th17 cells express IL-17A, IL-17F and IL-22 and develop in response to TGF-␤1 and IL-6 and by the induction or activation of the transcription factors STAT3, ROR␥t and ROR␣, with IL-21 and IL-23 providing subsequent reinforcement of this lineage (12). IL-1␤ enhances the development of Th17 cells (13), whereas IL-23 enhances the development of cells that express both IL-17A and IL-22 when TGF-␤1 is limiting (14 -16). Still more recently, a subset of IL-9-expressing T cells (i.e. "Th9" cells) has been implicated in autoimmunity (17)(18)(19). The development of these cells is directed by and is increased in the presence of IL-17E (known also as IL-25) (22). In light of recent insights into the pathogenicity of Th17 and Th9 cells and the longstanding appreciation of the protective effects of vitamin D, we reevaluated the impact of vitamin D signaling on the development of CD4 effector T cells. * This work was supported, in whole or in part, by National Institutes of Health Grants AI035783, AI057956, and DK064400 (to C. T. W.) and Postdoctoral Training Grant AR053458. This work was also supported b...

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Chronic reactivity of CD4(+) T cells to autoantigens and to components of the commensal flora drive destructive inflammation in a variety of mouse models of autoimmunity. Insight gained using these models is empowering translational research into human disease. Immunologists are trying to assign disease culpability to one of the ever-growing number of T helper (T(H)) cell subsets. Although recent discovery of the interleukin 17-producing T(H)-17 lineage appeared to supplant the pre-eminence of T(H)1 cells in promoting autoimmunity, the newest data defy simple paradigms. Here we speculate on the respective contributions to autoimmunity made by an increasingly complex list of T(H) subsets and argue that the T(H)1 phenotype may be staging a comeback.

Inflammatory bowel disease is associated with industrialization, and its incidence has increased markedly over time. The prospect of reversing these trends motivates the search for the agent(s) involved. Modernity entails several physical and behavioral modifications that compromise both the photosynthesis of cholecalciferol in the skin, and of its bioavailability. Although deficiency in this “vitamin” has therefore emerged as a leading candidate, and despite the publication of a randomized control trial that showed a trend towards statistically significant benefit in Crohn’s disease, its causal agency has yet to be demonstrated by an adequately powered study. We discuss the strengths and weaknesses of the case being made by epidemiologists, geneticists, clinicians and basic researchers, and consolidate their findings into a model that provides mechanistic plausibility to the claim. Specifically, converging data sets suggest that local activation of vitamin D coordinates the activity of the innate and adaptive arms of immunity, and of the intestinal epithelium, in a manner that promotes barrier integrity, facilitates the clearance of translocated flora and diverts CD4 T cell development away from inflammatory phenotypes. Since smoking is an important risk-altering exposure, we also discuss its newly established melanizing effect, as well as other emerging evidence linking tobacco use to immune function through vitamin D pathways.