Two lineages of immune cells that differentially express the vitamin D receptor
The Journal of Steroid Biochemistry and Molecular Biology. Volume 228, April 2023, 106253 https://doi.org/10.1016/j.jsbmb.2023.106253
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Abstract
Since 1983 it has been known that monocytes and activated T and B cells expressed the vitamin D receptor (VDR) and are therefore vitamin D targets. New data identified two lineages of immune cells that can be differentiated by the expression of the VDR. Monocytes, macrophages, neutrophils, and hematopoietic stem cells were mostly from VDR positive lineages. T cells, ILC1 and ILC3 were also largely VDR positive, which is consistent with the known effects of vitamin D as regulators of type-1 and type-3 immunity. Activation of the VDR negative T cells did not induce the expression of the VDR reporter, suggesting that perhaps only a subset of the T cells in the periphery express the VDR. When activated, the VDR negative T cells responded as if they were VDR knockout T cells in that they made more IFN-γ and proliferated faster than the VDR positive T cells. The ability of vitamin D to regulate immune function will depend on which cells express the VDR and a better understanding of the signals that regulate VDR expression in immune cells.
Introduction
The identification of the vitamin D receptor in immune cells resulted in new research to understand what the role of vitamin D was in controlling immune function [1], [2]. Vitamin D receptor (VDR) expression was found in human and mouse monocytes and in activated human and mouse T and B cells [1], [2]. The VDR is a nuclear receptor that in the presence of active vitamin D (1,25(OH)2D) binds as a heterodimer, with retinoid X receptor, on vitamin D response elements to regulate gene transcription [3]. The mechanisms whereby vitamin D regulates the immune system have been the focus of intense investigation. Determining the effect of vitamin D on immune function has been limited by a lack of reagents and tools to identify single cells that express the VDR. The development of a novel transgenic mouse that expresses a fluorescent protein under the control of the VDR promoter [4], has caused a shift in our understanding of the role of vitamin D in the immune system. The newer information suggests that there are two populations of immune cells in the periphery that can be differentiated by expression of the VDR. The implications of having some immune cells, but not all immune cells, express the VDR are discussed here.
Section snippets
Vitamin D and the VDR regulates gastrointestinal homeostasis
Vitamin D controls gastrointestinal homeostasis [5], [6], [7], [8]. In vivo, the effects of vitamin D on immunity depends on which cells express the VDR. Vitamin D regulates immunity in the gastrointestinal tract directly by regulating immune cells that express the VDR and indirectly by regulating epithelial cells that affect immune cell functions [5], [6], [9], [10]. Vitamin D deficiency is common in patients with the type-1/type-3 immune mediated disease, inflammatory bowel disease [11], [12]
VDR expression and immune cells
The kidney, small intestine and colon are tissues that constitutively express high amounts of the VDR [23]. Conversely, the spleen or thymus, that predominately contain immune cells, express relatively low amounts of the VDR [30]. The detection of VDR protein in immune cells is difficult because of the low amounts of the VDR and the reagents available are not sensitive enough to measure VDR expression in individual cells [4], [31].
Innate immune cells form the first line of defense against
Two lineages of immune cells that can be differentiated by expression of the VDR
VDR expression in most immune cells is low but can be increased by activation [52], [53]. A transgenic mouse that expressed the Cre enzyme in the VDR gene was developed and crossed with a VDR reporter mouse to lineage trace cells that express the VDR tdTomato (VDRtdTomato) fluorescent protein by flow cytometry [4]. The insertion of the Cre enzyme in the VDR gene disrupted one copy of the VDR gene [4]. The VDRtdTomato adult mice were visibly pink compared to their littermates that were VDRCre-/-
Vitamin D and hematopoiesis
Most hematopoietic stem cell progenitors in the adult mouse are from the VDR+ expressing lineage. There is evidence that vitamin D is important in the regulation of hematopoiesis. LSK from zebra fish proliferated more rapidly in the presence of 1,25(OH)2D and LSK from VDR KO mice were more long lived than their WT counterparts [58], [59]. 1,25(OH)2D treatment of BM cells promoted differentiation of progenitors into macrophages [60], [61], [62]. Conversely, the BM from VDR KO mice had fewer LSK,
Implications for VDR+ and VDR- immune cells in the periphery
Innate immune cells including monocytes, macrophages and neutrophils are from the VDR+ lineage, while ILC subtypes come from both VDR+ and VDR- lineages [4]. The ILC subtypes are the innate equivalents of helper T cells in the mucosal tissues and the combined ILC/Th response are required for immunity to viruses (ILC1/Th1), parasites (ILC2/Th2) and bacteria (ILC3/Th17) [64]. Vitamin D and 1,25(OH)2D inhibit Th1 and Th17 cells directly and indirectly [50], [65], [66], [67], [68], [69], [70].
Conclusions
Based on the expression of the VDR in most of the hematopoietic stem cells, vitamin D must be an important regulator of hematopoiesis. The immune system in the periphery is a mixture of cells from the VDR+ and VDR- expressing lineages (Fig. 1). Factors, such as vitamin D status, that regulate the proportion of VDR+ versus VDR- immune cells would impact the ability of vitamin D to regulate immune function. Understanding the mechanisms and controls over the regulation and expansion of the
References
- A. Wittke - Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation Arch. Biochem. Biophys. (2007)
- Y.D. Lin - Vitamin D is required for ILC3 derived IL-22 and protection from citrobacter rodentium infection Front Immunol. - (2019)
- K. Afsal et al. - 1, 25-dihydroxyvitamin D3 downregulates cytotoxic effector response in pulmonary tuberculosis
Int Immunopharmacol. (2018)
M. Cortes
Accumulation of the vitamin D precursor cholecalciferol antagonizes hedgehog signaling to impair hemogenic endothelium formation
Stem Cell Rep.
(2015)
Y. Kawamori
Role for vitamin D receptor in the neuronal control of the hematopoietic stem cell niche Blood
(2010)
K. Wakahashi
Vitamin D receptor–mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis
Blood
(2019)
M. Cortes
Developmental vitamin D availability impacts hematopoietic stem cell production
Cell Rep.
(2016)
E. Paubelle
Vitamin D receptor controls cell stemness in acute myeloid leukemia and in normal bone marrow
Cell Rep.
(2020)
Z. Fan
Bone marrow-derived hematopoietic stem and progenitor cells infiltrate allogeneic and syngeneic transplants
Am. J. Transpl.
(2014)
K. Muller et al.
1,25-dihydroxyvitamin D3 selectively reduces interleukin-2 levels and proliferation of human T cell lines in vitro
Immunol. Lett.
(1993)
C.M. Veldman et al.
Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system
Arch. Biochem Biophys.
(2000)
N. Karthaus
Vitamin D controls murine and human plasmacytoid dendritic cell function
J. Invest. Dermatol.
(2014)
M.D. Griffin
Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs
Biochem. Biophys. Res. Commun.
(2000)
P.T. Liu et al.
Human macrophage host defense against Mycobacterium tuberculosis
Curr. Opin. Immunol.
(2008)
Y. Wang et al.
Where is the vitamin D receptor?
Arch. Biochem. Biophys.
(2012)
J. Chen et al.
Vitamin D receptor expression controls proliferation of naive CD8+ T cells and development of CD8 mediated gastrointestinal inflammation
BMC Immunol.
(2014)
Y. Wang et al.
Where is the vitamin D receptor?
Arch. Biochem Biophys.
(2012)
M.T. Cantorna et al.
Aligning the paradoxical role of vitamin D in gastrointestinal immunity
Trends Endocrinol. Metab.
(2019)
J. Arora
Novel insight into the role of the vitamin D receptor in the development and function of the immune system
J. Steroid Biochem. Mol. Biol.
(2022)
J.W. Pike
Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand
Mol. Cell Endocrinol.
(2011)
D.M. Provvedini
1,25-dihydroxyvitamin D3 receptors in human leukocytes
Science
(1983)
A.K. Bhalla
Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation
J. Clin. Endocrinol. Metab.
(1983)
M.T. Cantorna et al.
Vitamin A and vitamin D regulate the microbial complexity, barrier function, and the mucosal immune responses to ensure intestinal homeostasis
Crit. Rev. Biochem. Mol. Biol.
(2019)
M.T. Cantorna
Vitamin D, immune regulation, the microbiota, and inflammatory bowel disease
Exp. Biol. Med. (Maywood)
(2014)
M.T. Cantorna
IBD: Vitamin D and IBD: moving towards clinical trials
Nat. Rev. Gastroenterol. Hepatol.
(2016)
Y.G. Zhang
Lack of Vitamin D receptor leads to hyperfunction of Claudin-2 in intestinal inflammatory responses
Inflamm. Bowel Dis.
(2019)
M. Froicu et al.
Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury
BMC Immunol.
(2007)
H.M. Pappa
Vitamin D status in children and young adults with inflammatory bowel disease
Pediatrics
(2006)
S. Katz
Osteoporosis in patients with inflammatory bowel disease: risk factors, prevention, and treatment
Rev. Gastroenterol. Disord.
(2006)
R. Dresner-Pollak
The BsmI vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients
Genet Test.
(2004)
J.D. Simmons
Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility
Gut
(2000)
L. Wang
Polymorphisms of the vitamin D receptor gene and the risk of inflammatory bowel disease: a meta-analysis
Genet Mol. Res
(2014)
L. Yang
Therapeutic effect of vitamin d supplementation in a pilot study of Crohn's patients
Clin. Transl. Gastroenterol.
(2013)
J. Li
Efficacy of vitamin D in treatment of inflammatory bowel disease: a meta-analysis
Med. (Baltim. )
(2018)
P. Miheller
Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn's disease patients
Inflamm. Bowel Dis.
(2009)
T.A. Kabbani
Association of vitamin D level with clinical status in inflammatory bowel disease: a 5-year longitudinal study
Am. J. Gastroenterol.
(2016)
M. Froicu
A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases
Mol. Endocrinol.
(2003)
M. Froicu et al.
Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice
Immunology
(2006)
The risk of 44 diseases at least double with poor Vitamin D Receptor
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