The vitamin D analog, TX527, promotes a human CD4+CD25highCD127low regulatory T cell profile and induces a migratory signature specific for homing to sites of inflammation.

Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Leuven, Belgium.
The Journal of Immunology (Impact Factor: 5.36). 01/2011; 186(1):132-42. DOI: 10.4049/jimmunol.1000695
Source: PubMed

ABSTRACT The use of hypocalcemic vitamin D analogs is an appealing strategy to exploit the immunomodulatory actions of active vitamin D in vivo while circumventing its calcemic side effects. The functional modulation of dendritic cells by these molecules is regarded as the key mechanism underlying their ability to regulate T cell reactivity. In this article, we demonstrate the capacity of the vitamin D analog, TX527, to target T cells directly. Microarray analysis of purified human CD3(+) T cells, cultured in the presence of TX527, revealed differential expression of genes involved in T cell activation, proliferation, differentiation, and migratory capacity. Accordingly, functional analysis showed a TX527-mediated suppression of the T cell proliferative capacity and activation status, accompanied by decreased expression of effector cytokines (IFN-γ, IL-4, and IL-17). Furthermore, TX527 triggered the emergence of CD4(+)CD25(high)CD127(low) regulatory T cells featuring elevated levels of IL-10, CTLA-4, and OX40 and the functional capacity to suppress activation and proliferation of effector T cells. Moreover, the vitamin D analog profoundly altered the homing receptor profile of T cells and their migration toward chemokine ligands. Remarkably, TX527 not only modulated skin-homing receptors as illustrated for the parent compound, but also reduced the expression of lymphoid organ-homing receptors (CD62L, CCR7, and CXCR4) and uniquely promoted surface expression of inflammatory homing receptors (CCR5, CXCR3, and CXCR6) on T cells. We conclude that TX527 directly affects human T cell function, thereby inhibiting effector T cell reactivity while inducing regulatory T cell characteristics, and imprints them with a specific homing signature favoring migration to sites of inflammation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The potential beneficial effects of supplementing vitamin D or treatment with pharmacological doses of vitamin D in the prevention or cure of diseases like type 1 (T1D) or type 2 diabetes (T2D) remains the subject of debate. Data from epidemiological and association studies clearly indicate a correlation between vitamin D deficiency and a higher prevalence of both forms of diabetes. In animal models, vitamin D deficiency predisposes to type 1 and type 2 diabetes, whereas high doses of vitamin D or its active hormonal form, 1,25-dihydroxyvitamin D, prevent disease. Large scale, randomized, blinded prospective studies however, remain lacking. Here we discuss the current literature on a role for vitamin D in diabetes. We propose, in particular, to avoid vitamin D deficiency in individuals at risk of developing T1D or T2D. Applying international guidelines on supplementation of vitamin D using small daily doses of vitamin D (500-1000IU) may contribute to reduce the burden of diabetes by preventing vitamin D deficiency. Any other recommendations are at present not supported by data. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Diabetes Research and Clinical Practice 02/2015; DOI:10.1016/j.diabres.2015.01.036 · 2.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D deficiency has been linked to an increased risk of a wide range of adverse health outcomes. The active form of vitamin D has an important role in calcium metabolism and in bone mineralisation, but the evidence for other health outcomes is mixed, with the strongest effects seen in the weakest epidemiological study designs. There are plausible pathways whereby vitamin D deficiency can impair immune function, resulting in both overactivity and increased risk of autoimmune disease, as well as immune suppression with poorer resistance to infection. Vitamin D status may influence the bacterial flora that constitute the microbiome and affect immune function through this route. Exposure of the skin to ultraviolet radiation causes the production of a range of chemicals, including vitamin D, and new research is exploring possible vitamin D-independent immunomodulatory pathways.
    01/2014; 6:118. DOI:10.12703/P6-118
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This review summarizes and integrates research on vitamin D and CD4(+) T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene-environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4(+) T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4(+) T lymphocytes is summarized to support the thesis that calcitriol is sunlight's main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3(+)CD4(+) T-regulatory cell and CD4(+) T-regulatory cell type 1 (Tr1) cell functions, and a Th1-Tr1 switch. The proposed Th1-Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell-cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease.
    Frontiers in Immunology 01/2015; 6:100. DOI:10.3389/fimmu.2015.00100

Full-text (2 Sources)

Available from
May 22, 2014