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

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+CD25highCD127low 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.

Dietary Supplementation With High Doses of Regular Vitamin D3 Safely Reduces Diabetes Incidence in NOD Mice When Given Early and Long Term

“…Despite some early studies suggesting a protective effect of vitamin D, a meta-analysis by Zipitis and Akobeng (22) concluded that supplementing pregnant women with vitamin D (36) and triggering the emergence of Tregs with the functional capacity to suppress activation and proliferation of Teff cells (37,38). Here, we report that upon vitamin D 3 supplementation, these Treg (subsets) preferentially accumulate in draining PLN and pancreatic islets.…”

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

“…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.…”

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

“…Although early response to vitamin D in a monocytic cell line is characterized by activation of gene expression, late response is characterized by the closing of the affected chromatin and similar proportion of up-and down-regulated genes (39). Equal proportion of up-and down-regulated genes has also been described in primary T cells after 10 d of exposure to a vitamin D analog (51). We observed similar distribution with 59% (2,050/3,460) of affected probes being down-regulated.…”

“…Patterns of VDR binding (20,35) and gene expression (39,51) in cell lines and healthy subjects have suggested an effect of vitamin D on metabolic and signaling pathways crucial for cell survival, growth, and proliferation. Our data confirm that these pathways are also affected in vivo in CD4+ T cells, mediating the protective effect of the vitamin D supplementation in experimental autoimmune disease.…”