Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function

Urry, Zoë; Xystrakis, Emmanuel; Richards, David F.; McDonald, John G.; Sattar, Zahid; Cousins, David J.; Corrigan, Christopher; Hickman, Emma; Brown, Zarin; Hawrylowicz, Catherine M.

doi:10.1172/jci32354

Cited by 136 publications

(176 citation statements)

References 66 publications

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“…This approach is especially suited to ongoing chronic diseases such as asthma that occur at high prevalence, where a simple treatment such as vitamin D supplementation would be relatively safe, acceptable to patients, and cost effective. The present study aimed to investigate the capacity of 1α25VitD3 to promote Treg cells and whether dose-dependent limitations exist.Early indications from clinical studies suggest vitamin D treatment of patients enhances T-cell expression of IL-10 in vivo, although data on the impact on Foxp3 + Treg cell frequencies in human peripheral blood are less clear [12,[23][24][25][26]. Here, we demonstrate that the active form of vitamin D3 increases the frequency of both IL-10 + and Foxp3 + cells in cultures of human peripheral blood derived CD4 + T cells.…”

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confidence: 59%

“…An unusual dose response was observed in vitro with 1α25VitD3 at the very highest concentration tested (10 −6 M 1α25VitD3) resulting in considerably lower IL-10 secretion than the optimal concentrations of 10 −7 M and 10 −8 M 1α25VitD3 [12]. Here, we analyzed this dose response further and investigated whether IL-10 was being synthesized by Foxp3 positive or negative T cells in response to 1α25VitD3 in culture.Human peripheral blood CD4 + T cells were stimulated with anti-CD3, IL-2, and IL-4 under conditions previously determined to optimally induce IL-10-Treg cells [12]. The expression of Foxp3 and IL-10 in the presence or absence of 1α25VitD3 was determined by flow cytometry.…”

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confidence: 93%

“…Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4 + IL-10 secreting Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13,14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression in CD3 + CD4 + T cells [12], and restored the impaired steroid-induced IL-10 response in CD4 + cells in vitro [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…asthma patients [12,14]. An unusual dose response was observed in vitro with 1α25VitD3 at the very highest concentration tested (10 −6 M 1α25VitD3) resulting in considerably lower IL-10 secretion than the optimal concentrations of 10 −7 M and 10 −8 M 1α25VitD3 [12]. Here, we analyzed this dose response further and investigated whether IL-10 was being synthesized by Foxp3 positive or negative T cells in response to 1α25VitD3 in culture.…”

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confidence: 95%

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The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4 + T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3 + regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3 + and IL-10 + CD4 + T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3 + and IL-10 + T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3 + Treg cells over their Foxp3 − T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3 + expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4 + Foxp3 + T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10 + and Foxp3 + Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.Keywords: 1α,25-Dihydroxyvitamin D3 r Asthma r Immune regulation r Regulatory T cells Supporting Information available online IntroductionConsiderable interest exists in the therapeutic potential of regulatory T (Treg) cells to treat a range of immune-mediated patholoCorrespondence: Dr. Catherine M. Hawrylowicz e-mail: catherine.hawrylowicz@kcl.ac.uk gies in humans. This is partly based on evidence obtained from animal models of human disease demonstrating the capacity of Treg cells to control transplant rejection, and to successfully treat autoimmune and allergic disease [1]. Two broad therapeutic * These authors contributed equally to this work. [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4 + IL-10 secreting Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13,14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression in CD3 + CD4 + T cells [12], and restored the impaired steroid-induced IL-10 response in CD4 + cells in vitro [14,15].The present study was designed to further investigate the mechanisms underlying the therapeutic potential of 1α25VitD3 in the context of asthmatic disease, and to determine effects on the induction of both IL-10 + and Foxp3 + T cells. Specifically, we have examined the effects of 1α25VitD3 on total, unfractionated CD4 + T-cell populations, r...

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confidence: 59%

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confidence: 93%

Section: Introductionmentioning

confidence: 99%

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confidence: 95%

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The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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“…Treatment of naive CD4 + T-cells with 1,25(OH) 2 D potently induces the development of Treg (112) , and this may exert beneficial effects in autoimmune disease and host-graft rejection (113)(114)(115) . Although, 1,25(OH) 2 D can stimulate Treg development directly via VDR expression by CD4 + T-cells (116,117) , it may also act via effects on antigen-presenting cells. Specifically, as outlined earlier, the ability of 1,25(OH) 2 D to induce an immature DC phenotype will promote tolerogenic Treg activity in CD4 + T-cells (118)(119)(120) .…”

Section: Vitamin D and Adaptive Immunitymentioning

confidence: 99%

Vitamin D and immune function: an overview

2011

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Immunomodulatory actions of vitamin D have been recognised for over a quarter of a century, but it is only in the last few years that the significance of this to normal human physiology has become apparent. Two key factors have underpinned this revised perspective. Firstly, there are increasing data linking vitamin insufficiency with prevalent immune disorders. Improved awareness of low circulating levels of precursor 25-hydroxyvitamin D in populations across the globe has prompted epidemiological investigations of health problems associated with vitamin D insufficiency. Prominent among these are autoimmune diseases such as multiple sclerosis, type 1 diabetes and Crohn's disease, but more recent studies indicate that infections such as tuberculosis may also be linked to low 25-hydroxyvitamin D levels. The second factor expanding the link between vitamin D and the immune system is our improved knowledge of the mechanisms that facilitate this association. It is now clear that cells from the immune system contain all the machinery needed to convert 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D, and for subsequent responses to 1,25-dihydroxyvitamin D. Mechanisms such as this are important for promoting antimicrobial responses to pathogens in macrophages, and for regulating the maturation of antigen-presenting dendritic cells. The latter may be a key pathway by which vitamin D controls T-lymphocyte (T-cell) function. However, T-cells also exhibit direct responses to 1,25-dihydroxyvitamin D, notably the development of suppressor regulatory T-cells. Collectively these observations suggest that vitamin D is a key factor linking innate and adaptive immunity, and both of these functions may be compromised under conditions of vitamin D insufficiency. DEFB4, b-defensin 2; Gc, group-specific component; IBD, inflammatory bowel disease; NOD2, non-obese diabetic

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Role of Treg in immune regulation of allergic diseases

et al. 2010

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Allergy is a Th2-mediated disease that involves the formation of specific IgE antibodies against innocuous environmental substances. The prevalence of allergic diseases has dramatically increased over the past decades, affecting up to 30% of the population in industrialized countries. The understanding of mechanisms underlying allergic diseases as well as those operating in non-allergic healthy responses and allergen-specific immunotherapy has experienced exciting advances over the past 15 years. Studies in healthy non-atopic individuals and several clinical trials of allergen-specific immunotherapy have demonstrated that the induction of a tolerant state in peripheral T cells represent a key step in healthy immune responses to allergens. Both naturally occurring thymus-derived CD4 1 CD25 1 FOXP3 1 Treg and inducible type 1 Treg inhibit the development of allergy via several mechanisms, including suppression of other effector Th1, Th2, Th17 cells; suppression of eosinophils, mast cells and basophils; Ab isotype change from IgE to IgG4; suppression of inflammatory DC; and suppression of inflammatory cell migration to tissues. The identification of the molecules involved in these processes will contribute to the development of more efficient and safer treatment modalities.Key words: Allergy . Allergen-specific immunotherapy . Tolerance . Treg IntroductionThe immune system is a complex interactive network with the capacity to protect the host from a broad range of pathogens while keeping a state of tolerance to self and innocuous non-self antigens. Immune tolerance-related diseases such as allergy, autoimmunity, tumor tolerance and rejection of organ transplants arise as a direct consequence of dysregulated immune responses. The main clinical manifestations of allergy encompass allergic rhinitis, allergic asthma, food allergy, atopic eczema/ dermatitis and anaphylaxis. Currently, allergen-specific immunotherapy (allergen-SIT) by administration of increasing doses of allergen extracts remains as the single curative treatment of allergic diseases with the potential to modify the course of the disease [1].Adoptive transfer experiments in mouse models of allergy and asthmatic inflammation have shown that Treg are essential for the induction and maintenance of immune tolerance to allergens [2]. In humans, studies on immune responses to allergens in healthy individuals have demonstrated the existence of dominant Treg subsets specific to common environmental allergens [3]. In addition, allergen-SIT represents the only clinically established treatment that induces antigen-specific Treg and peripheral tolerance with the capacity to restore homeostasis in human subjects [3][4][5][6][7][8]. Accordingly, active immune regulation through allergen-specific Treg emerges as a potential therapeutic option 1232Review in the prevention and cure of allergic diseases. The aim of this review is to discuss the immune regulation mechanisms operating in allergic diseases with a focus on the role of Treg in the generation of tolerance agai...

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Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function

Cited by 136 publications

References 66 publications

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

Vitamin D and immune function: an overview

Role of Treg in immune regulation of allergic diseases

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Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function

Cited by 136 publications

References 66 publications

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

Vitamin D and immune function: an overview

Role of Treg in immune regulation of allergic diseases

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The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells