We describe a reporter mouse strain designed to fate-map cells that have activated IL-17A. Here we show that TH17 cells show distinct plasticity in different inflammatory settings. Chronic inflammatory conditions in EAE caused a switch to alternative cytokines in TH17 cells, whereas acute cutaneous infection with Candida albicans, did not result in deviation of TH17 to alternative cytokine production, although IL-17A production was shut off in the course of the infection. During development of EAE, IFN-γ and other pro-inflammatory cytokines in the spinal cord were produced almost exclusively by ‘ex-TH17’ cells whose conversion was driven by IL-23. Thus, this model allows relating the actual functional fate of effector T cells to TH17 developmental origin irrespective of IL-17 expression.

IMPORTANCE Asthma and wheezing begin early in life, and prenatal vitamin D deficiency has been variably associated with these disorders in offspring. OBJECTIVE To determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood. DESIGN, SETTING, AND PARTICIPANTS The Vitamin D Antenatal Asthma Reduction Trial was a randomized, double-blind, placebo-controlled trial conducted in 3 centers across the United States. Enrollment began in October 2009 and completed follow-up in January 2015. Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were randomized at 10 to 18 weeks' gestation. Five participants were deemed ineligible shortly after randomization and were discontinued. INTERVENTIONS Four hundred forty women were randomized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D, and 436 women were randomized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D. MAIN OUTCOMES AND MEASURES Coprimary outcomes of (1) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and (2) third trimester maternal 25-hydroxyvitamin D levels. RESULTS Eight hundred ten infants were born in the study, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24.3%; 95% CI, 18.7%-28.5%) in the 4400-IU group vs 120 of 401 (30.4%, 95% CI, 25.7%-73.1%) in the 400-IU group (hazard ratio, 0.8; 95% CI, 0.6-1.0; P = .051). Of the women in the 4400-IU group whose blood levels were checked, 289 (74.9%) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 (34.0%) in the 400-IU group (difference, 40.9%; 95% CI, 34.2%-47.5%, P < .001). CONCLUSIONS AND RELEVANCE In pregnant women at risk of having a child with asthma, supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women. The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance; however, the study may have been underpowered. Longer follow-up of the children is ongoing to determine whether the difference is clinically important.

Background: Programming of the immune system during fetal development can influence asthma-related risk factors and outcomes in later life. Vitamin D is a well-recognized immune modulator, and deficiency of this nutrient during pregnancy is hypothesized to influence disease development in offspring. Objective: We sought to investigate the effect on neonatal immunity of maternal supplementation with 4400 IU/d vitamin D 3 during the second and third trimesters of pregnancy by using a subset of cord blood samples from a randomized, doubleblind, placebo-controlled clinical trial (the Vitamin D Antenatal Asthma Reduction Trial). Methods: Cord blood samples from neonates born to mothers supplemented with 4400 IU/d (n 5 26) or 400 IU/d (n 5 25) of vitamin D 3 were analyzed for immune cell composition by flow cytometry, Toll-like receptor (TLR) expression by quantitative PCR, and cytokine secretion after stimulation with mitogenic, TLR, and T-cell stimuli by cytometric bead array. Responsiveness to the glucocorticoid dexamethasone was determined. Results: Supplementation of mothers with 4400 IU of vitamin D 3 resulted in an enhanced broad-spectrum proinflammatory cytokine response of cord blood mononuclear cells to innate and mitogenic stimuli (P 5 .0009), with an average 1.7-to 2.1-fold increase in levels of several proinflammatory cytokines (GM-CSF, IFN-g, IL-1b, IL-6, and IL-8) across stimuli, a higher gene expression level of TLR2 (P 5 .02) and TLR9 (P 5 .02), a greater than 4-fold increase in IL-17A (P 5 .03) production after polyclonal T-cell stimulation, and an enhanced IL-10 response From a the MRC and Asthma UK Centre for Allergic Mechanisms in Asthma, King's College London, London;

The prevalence of vitamin D insufficiency and deficiency has increased markedly in recent decades to current epidemic levels (Hyppönen E, et al. Am J Clin Nutr 2007;85:860-868). In parallel, there has been an increase in the incidence of a range of immune-mediated conditions ranging from cancer to autoimmune and respiratory diseases, including chronic obstructive pulmonary disease and asthma (Holick MF. N Engl J Med 2007;357:266-281; Finklea et al. Adv Nutr 2011;2:244-253). There is also an association with increased respiratory infections, which are the most common cause of asthma exacerbations (Finklea et al. Adv Nutr 2011;2:244-253). Together, this has resulted in considerable interest in the therapeutic potential of vitamin D to prevent and improve treatment of asthma and other respiratory diseases. To this end, data from clinical trials involving supplementation with active vitamin D, or more commonly a precursor, are starting to emerge. This review considers mechanisms by which vitamin D may act on the immune system to dampen inappropriate inflammatory responses in the airway while also promoting tolerance and antimicrobial defense mechanisms that collectively maintain respiratory health.

Monocytes are mononuclear phagocytes that can differentiate to a variety of cell fates under the influence of their microenvironment and hardwired commitment. We found that inhibition of TRPM8 in human blood CD14+ monocytes during a critical 3‐h window at the beginning of their differentiation into macrophages led to enhanced survival and LPS‐driven TNFα production after 24 h. TRPM8 antagonism also promoted LPS‐driven TNFα production in CD14+ monocytes derived from the intestinal mucosa. Macrophages that had been derived for 6 days under blockade of TRPM8 had impaired phagocytic capacity and were transcriptionally distinct. Most of the affected genes were altered in a way that opposed normal monocyte to macrophage differentiation indicating that TRPM8 activity promotes aspects of this differentiation programme. Thus, we reveal a novel role for TRPM8 in regulating human CD14+ monocyte fate and function.

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Professional antigen‐presenting cells (APCs) comprise dendritic cells (DCs), macrophages (MΦs) and B cells. Collectively, they initiate an adaptive immune response to pathogens, shape the nature of this response and contribute to its regulation and termination. They also play key roles in maintenance of tolerance to self‐antigens. Only DCs are able to activate naïve T cells, and from this pivotal position at the initiation of a response, they are able to shape the differentiation of the T cells towards different functional fates and instruct trafficking of these cells to sites of infection. In contrast, MΦs and B cells re‐stimulate T cells, previously activated by DCs in an antigen‐specific manner. They function to amplify the initial DC‐activated response and to elicit the targeted production of T cell‐derived factors required for antibody production by B cells and the enhanced microbicidal activity of MΦs. Key Concepts Cells that express MHC class II under resting conditions are often termed ‘professional’ antigen‐presenting cells (APCs). Professional APCs comprise dendritic cells (DCs), macrophages (MΦs) and B cells. Many tissue MΦs are derived from embryonic precursors and locally renew; DCs, B cells and some MΦs are derived by distinct pathways, in adult bone marrow. Only DCs can activate naïve T cells. DC‐derived signals shape the differentiation of CD4 T cells towards different functional subsets and can influence the trafficking of the cells generated to different tissues. DCs can also induce tolerance via deletion, anergy and generation of T cells with regulatory properties. Small numbers of DCs carrying self‐antigens constitutively migrate to secondary lymphoid organs (SLOs), but in the absence of exposure to infection‐associated ‘danger’ signals they express low levels of co‐stimulatory molecules and fail to stimulate adaptive immunity. In infection, DCs undergo maturation in response to danger signals; mature DCs presenting foreign antigens and expressing high levels of co‐stimulatory molecules induce effector T cell responses. B cells present antigen to DC‐activated T cells in order to trigger the targeted release of T cell derived factors that are required by B cells for production of high‐quality antibodies (‘T cell help’). MΦs present antigen to DC‐activated T cells in order to trigger the targeted release of cytokines that activate the MΦ for enhanced microbicidal activity, reducing collateral tissue damage caused by toxic metabolites involved in pathogen killing.

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