More than thirty years ago functions of vitamin D other than its beneficial effects on calcium homeostasis and bone metabolism have been identified, mainly in relation to its antiproliferative effects on cancer cells. Notably, vitamin D deficiency has been associated with a number of pathological conditions, including infections, autoimmune and allergic diseases. Vitamin D, and its metabolites, are actively involved in the regulation of innate and adaptive immune responses. Vitamin D signals through the vitamin D receptor (VDR), a specific zinc-finger nuclear receptor. The functions of vitamin D are characterized as genomic, mediated through the VDR transcriptional effects inside the cell nucleus, and non-genomic, when the VDR induces rapid signaling, situated on the cell membrane and/or cytoplasm. Emerging evidence supports the notion that vitamin D enhances immunity, providing protection towards pathogens, while, concomitantly, it exerts immunosuppressive effects by preventing the detrimental effects of prolonged inflammatory responses to the host. Still, the precise molecular mechanisms involved in vitamin D's genomic and non-genomic actions remain incompletely defined. Moreover, it is unclear whether vitamin D actions require the synergistic activation of other mediators, such as nuclear membrane receptors. Understanding the biology of vitamin D and the molecular pathways utilized will pave the way for the design of more effective therapeutic strategies. In this review, we present the recent genomic and non-genomic effects of vitamin D from an immunological perspective with a focus on immune-mediated diseases.

Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4 + T cells that express the Tr1-cell-associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells. Moreover, mechanistic studies reveal that activin-A signaling induces the activation of the transcription factor interferon regulatory factor (IRF4), which, along with the environmental sensor aryl hydrocarbon receptor, forms a multipartite transcriptional complex that binds in IL-10 and ICOS promoter elements and controls gene expression in human CD4 + T cells. In fact, IRF4 silencing abrogates activin-A-driven IL10 and ICOS up-regulation and impairs the suppressive functions of human activin-A-induced Tr1-like (act-A-iTr1) cells. Importantly, using a humanized mouse model of allergic asthma, we demonstrate that adoptive transfer of human act-A-iTr1 cells, both in preventive and therapeutic protocols, confers significant protection against cardinal asthma manifestations, including pulmonary inflammation. Overall, our findings uncover an activin-A-induced IRF4-aryl hydrocarbon receptor (AhR)-dependent transcriptional network, which generates suppressive human Tr1 cells that may be harnessed for the control of allergic diseases.cytokines | allergic inflammation | immune regulation | activin-A | human T regulatory cells

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In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A–induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements onEntpd1andNt5e(encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.

Viruses are associated with different NP bacterial colonization patterns. Observed pathogens' associations may play a role in disease, and continuous surveillance is required to follow possible effects of interventions such as vaccines.

The IP-10 assay could be useful in improving the diagnosis of LTBI in patients aged <5 years in combination with existing interferon-gamma release assays.

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