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,25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells1
,
*
Department of Immunology, DNAX Research Institute, Palo Alto, CA 94304;
Department of Immunology, Erasmus University and University Hospital Rotterdam, Rotterdam, The Netherlands;
Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone
with beneficial effects on Th1 mediated autoimmune diseases. Although
the inhibitory effects of vitD3 on macrophages and dendritic cells are
well documented, any direct effects of vitD3 on Th cell development are
not clearly defined. Using CD4+Mel14+ T cells
derived from mice on a BALB/c and a C57BL/6 genetic background we
examined the effect of vitD3 on Th cell development. We demonstrated
that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-
production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10
production). These effects were observed in cultures driven with
splenic APC and Ag, as well as with anti-CD3 and anti-CD28
alone, indicating that CD4+ cells can also be direct
targets for vitD3. The enhanced Th2 development by vitD3 was found in
both BALB/c and C57BL/6 mice. An increased expression of the
Th2-specific transcription factors GATA-3 and c-maf
correlated with the increased production of Th2 cytokines after vitD3
treatment. The vitD3-induced effects were largely mediated via IL-4,
because neutralization of IL-4 almost completely abrogated the
augmented Th2 cell development after vitD3 treatment. These findings
suggest that vitD3 acts directly on Th cells and can, in the absence of
APC, enhance the development of a Th2 phenotype and augment the
expression of the transcription factors c-maf and
GATA-3. Our findings suggest that the beneficial effects of vitD3 in
autoimmune diseases and transplantation operate through prevention of
strong Th1 responses via the action on the APC, while simultaneously
directly acting on the T cell to enhance Th2 cell
development. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and lymphotoxin
and is important for protection against intracellular pathogens and has
also been associated with autoimmune pathologies (3). The
Th2 subset produces IL-4, IL-5, and IL-13 and is implicated in
eradicating helminth and other extracellular parasites, as well as
being involved in allergic manifestations. The development of
CD4+ T cells into either Th1 or Th2 cells
determines the outcome of an immune response, and is primarily directed
by cytokines; Th1 cells develop in response to IL-12, whereas IL-4
induces the development of Th2 cells (4, 5, 6, 7). Studies on
the molecular mechanisms of Th development have demonstrated the
importance of Th1 (T-bet) and Th2 (c-maf and GATA-3)
specific transcription factors in the regulation of the Th1/Th2
balance. c-maf increases the expression of IL-4
(8), whereas GATA-3 can induce the expression of a
wide range of Th2-specific cytokines (9, 10).
Furthermore, forced expression of GATA-3 can elicit the production
of Th2-specific cytokines in developing and committed Th1 cells, and
inhibit IFN- production (11, 12, 13). The Th1-specific
transcription factor T-bet induces the expression of IFN-, and
represses IL-4 and IL-5 production in developing and committed Th2
cells (14). Beside the dominant role of cytokines in Th development, additional factors have been described which affect the Th1-Th2 balance, e.g., the Ag dose, the strength of TCR signaling, and costimulatory signals (7). Furthermore, a number of nonprotein compounds have been reported to influence Th cell development, such as glucocorticoids, eicosanoids, and vitamins (15, 16, 17, 18, 19).
1,25-Dihydroxyvitamin D3
(vitD3)3 is a
seco-steroid hormone that is not only involved in mineral and skeletal
homeostasis, but also regulates the differentiation, growth, and
function of a broad range of cells, including cells of the immune
system (20). VitD3 acts through its receptor, the nuclear
vitD3 receptor, which in turn acts as a transcription factor by binding
to distinct vitD3 receptor responsive elements that are present
in the promoter regions of target genes. VitD3 also modulates gene
transcription by affecting the activity of transcription factors, such
as the NF-AT, NF-
B, and SMAD families of transcription
factors (21, 22, 23). Activated macrophages possess the enzyme
1--hydroxylase that allows for the production of vitD3, which
suggests a role for this endogenously produced steroid hormone in
regulation of immune responses (24). Furthermore, vitD3
has been demonstrated to prevent Th1-mediated autoimmune diseases in
animal models for experimental allergic encephalomyelitis, systemic
lupus erythematosus, and type I diabetes (25, 26, 27). A
number of studies have demonstrated that vitD3 modulates the activity
of monocytes/macrophages and dendritic cells (16, 28, 29, 30, 31, 32).
It was found that vitD3 inhibits the differentiation and maturation of
DC; reduces the expression of MHC class II, CD40, CD80, and CD86; and
inhibits the secretion of IL-1, IL-6, TNF-, and IL-12
(30, 31, 32). In vitro stimulation in the presence of APC,
showed a vitD3-induced reduction of IFN- production, whereas the Th2
compartment was not affected (26, 33, 34). In vivo
administration of vitD3 resulted in an increase in IL-4 expression
(35) and production (36), with a concomitant
reduction of IFN- levels. The inhibition of Th1 development by vitD3
is thought to be primarily mediated via its action on the APC as a
consequence of reduced IL-12 production after vitD3 treatment
(31).
These studies suggest that the vitD3-induced switch from Th1 to Th2 may be attributable to its ability to modulate the APC. However, it is unclear to date whether the effects of vitD3 on Th cell development are mediated solely via effects on the APC (e.g., reduced IL-12) or whether CD4+ cells are also direct targets. It has been shown that vitD3 can act directly on T cells by inhibiting T cell proliferation (37). However, no studies have yet addressed whether vitD3 has any direct effects on CD4+ T cells to affect their subsequent development into Th1 and Th2 cells. In this study we describe that vitD3 has a direct effect on CD4+ T cells to enhance the development of Th2 cells in the absence of APC, producing IL-4, IL-5, and IL-10, and to augment the expression of GATA-3 and c-maf.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DO.11.10 mice transgenic for an
OVA323–339-specific 
TCR were used as a
source of Ag-specific T cells (38). BALB/cAnN (Taconic
Farms, Germantown, NY) and C57BL/6J (The Jackson Laboratory, Bar
Harbor, ME) mice were used to provide splenic APCs or T cells. All mice
were housed under specific pathogen-free conditions and were used
between 8 and 12 wk of age.
Reagents
mAb used in culture were anti-IL-4 (11B11)
(39), anti-IL-12 (clone C17.8.20, a kind gift of G.
Trinchieri, Ref. 40), and anti-IFN- (XMG 1.2, J.
Abrams, DNAX, Palo Alto, CA). IL-2 and IL-4 were obtained from DNAX.
IL-12 was purchased from R&D Systems (Minneapolis, MN). Anti-mouse CD3
(145-2C11) and anti-CD28 (37.51) mAb used for T cell stimulation
were purchased from BD PharMingen (San Diego, CA). mAb used for T cell
preparation were anti-B220, anti-CD8, anti-Mac-1,
anti-CD4-FITC, and anti-L-selectin-PE (all mouse specific, BD
PharMingen). mAb used for intracellular staining were anti-IFN-
(clone XMG1.2), anti-IL-4 (11B11), anti-IL-10 (JES5-16E3),
anti-IL-5 (TRFK-5) and isotype controls (all from BD
PharMingen).
Tissue culture medium used was RPMI 1640 (J.R. Scientific, Woodland, CA) supplemented with 10% FCS (heat inactivated for 30 min at 56°C, J.R. Scientific), 0.05 mM 2-ME (Sigma, St. Louis, MO), 10 mM HEPES buffer (Life Technologies, Grand Island, NY), 100 U/ml penicillin (Life Technologies) and 100 µg/ml streptomycin (Life Technologies), 2 mM L-glutamine (BioWhittaker, Walkersville, MD), and 1 mM sodium pyruvate (BioWhittaker). 1,25(OH)2-vitamin D3 was purchased from Biomol (Plymouth Meeting, PA). OVA peptide was used as a synthetic peptide encoding chicken OVA323–339 (Biosynthesis, Lewisville, TX).
Preparation of T cells and APC
CD4+ T cells were enriched by negative
depletion using a mixture of anti-CD8, anti-B220, and
anti-Mac-1 mAb, followed by goat-anti-rat Ig coated beads
(Biomag; Polysciences, Warrington, PA) as described previously
(13). Enriched CD4+ T cells were
then further purified using a FACStarPlus flow
cytometer (BD Biosciences, San Jose, CA) to achieve >99% naive
CD4+ T cells on the basis of bright Mel-14, CD4
staining (41). Staining did not alter the function of the
T cells (data not shown).
Stimulation of transgenic CD4+ T cells for cytokine production
Primary stimulations of CD4+ T cells
(2.5 x 105/well) were conducted using OVA
peptide (0.6 µM) and RBC-lysed spleen cells (5 x
106/well, 3000 rad) as APC in a total volume of 2
ml in 24-well plates. In some cases, Ag and APC were replaced by
cross-linked anti-CD3 (10 µg/ml) and soluble anti-CD28 (1
µg/ml) mAb, and 1.5 x 106 cells were used
per 2-ml well in 24-well plates. Cultures received only medium (i.e.,
neutral) or vitD3 (4 x 10-8 M). In
addition, some cultures were supplemented with anti-IL-4,
anti-IL-12, or anti-IFN- mAb (10 µg/ml) to block
endogenously produced cytokines. The dose of vitD3 is in the range of
that used in other studies (18, 30, 31) and did not induce
apoptosis or strong inhibition of Th cell proliferation. Cells were
split on day 3, and harvested on day 7, washed twice, counted, and
restimulated as described for the primary stimulation with the addition
of 10 ng/ml IL-2. Restimulation of the cells in the APC-free system was
with 2 µg/ml anti-CD3, 2 µg/ml anti-CD28 mAb, and 10
ng/ml IL-2.
Cytokine assays
IL-4 and IFN- sandwich ELISA assays were performed as
previously described (42). The method for intracellular
cytokine staining was as reported (43). Briefly, cultured
CD4+ cells were stimulated with 10 ng/ml IL-2, 1
µg/ml PMA (Sigma), and 2 µg/ml ionomycin (Sigma) at
106 cells/ml for 2 h at 37°C. After 2
h, 10 µg/ml brefeldin A (Epicentre Technologies, Madison, WI) was
added and the cells were incubated for another 2 h. The cells were
then fixed with 2% formaldehyde, permeabilized with 0.5% saponin, and
stained as described before (43). Samples were analyzed on
a FACScan flow cytometer (BD Biosciences) and analyzed using CellQuest
software (BD Biosciences).
RNase protection assay
RNA was prepared using the Rnazol B method (Cinna/Biotecx Laboratories, Houston, TX) according to the manufacturer’s instructions, and 7 µg RNA was used to perform the RNase protection assay. Riboprobes of GATA-3, T-bet, and 18S inserted in the pGEM vector were prepared by linearization with HindIII. c-maf, inserted in the pBSK vector, was linearized using BglII before use in the RNase protection assay. The expected band size was as follows. GATA-3, 418 bp; c-maf, 329 bp; T-bet, 290 bp; and 18S, 187 bp. The probes (0.1 µg each) were labeled with 32P using an in vitro transcription kit (BD PharMingen). Samples were run on a 5% acrylamide gel and were visualized using phosphorimaging (Molecular Dynamics, Sunnyvale, CA). Transcript levels were quantified using ImageQuant software (Molecular Dynamics).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To address the effect of vitD3 on Th cell development we cultured
naive TCR-transgenic CD4+ DO11.10 T cells with
splenic APC and OVA peptide under neutral conditions (medium alone, no
additions) or medium supplemented with vitD3. After two rounds of
stimulation, the cytokine profile for intracellular cytokine production
was determined by flow cytometry upon restimulation. As depicted in
Fig. 1
A, vitD3-driven Th cells
showed an increased frequency of IL-4-producing cells and a reduction
in the number of IFN--producing cells as compared with cells grown
under neutral conditions. Consistent with augmented Th2 development
after culture with vitD3, an increase in IL-10- and IL-5-producing Th
cells was also detected. Culture of Th cells under Th2
(IL-4/anti-IL-12) polarizing conditions resulted in a more
pronounced Th2 phenotype (55% IL-4-producing cells) as compared with
cells cultured with vitD3 (41% IL-4-producing cells). As shown in Fig. 1B, the effect of vitD3 on the cytokine production reflects
augmented Th2 development with reduced IFN- and increased IL-4
production, which is in accordance with the cytokine profile as
determined by flow cytometry. Although the effects of vitD3 on Th
development were more pronounced after repeated stimulation, a single
stimulation was sufficient to demonstrate enhanced development of Th2
cells by vitD3 (Fig. 1C).
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Because IL-4 is the major cytokine that directs the development of
Th2 cells, we determined whether IL-4 played a role in the observed
augmented development of Th2 cells after in vitro culture in the
presence of vitD3. To examine this we included cultures in which IL-4
was neutralized during the entire culture period. Fig. 2 shows that addition of anti-IL-4
mAb to the cultures containing vitD3 completely abrogated the
development of Th2 cells producing IL-4. In fact, when IL-4 was
neutralized, the frequency of IL-4-producing cells cultured with vitD3
was similar to that observed when cells were cultured under neutral
conditions in the presence of anti-IL-4 mAb (Fig. 2). These data
indicate that IL-4 is required for the vitD3-induced effects on Th
cells development. Addition of anti-IL-4 mAb resulted in a
significant increase in the frequency of IFN--producing cells.
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A number of studies have reported vitD3-induced reduction of IL-2
and IFN- production, but only in some cases a subsequent enhancement
of Th2-type cytokines by T cells in the presence of APC (18, 33, 44). To determine whether vitD3 also has a direct effect on Th
cell development independently of APC related effects we activated
naive CD4+ Mel14+ T cells
with plate bound anti-CD3 and soluble anti-CD28 mAb in the
presence or absence of vitD3. The cells were repeatedly stimulated, and
their cytokine profile was assessed after 3 wk in culture. Fig. 3A shows that purified naive
CD4+ Mel14+ T cells
obtained from BALB/c mice stimulated in the absence of APC develop into
a highly polarized Th2 population when cultured with vitD3, similarly
to APC-driven cultures. The frequency of IL-4-producing cells was
enhanced from 8.0 to 55.8%. In accordance with this, the frequency of
IL-10- and IL-5-producing cells was also dramatically increased,
whereas the frequency of IFN--producing cells was reduced.
The frequency of IL-4-producing cells after culture with vitD3 was
similar to cultures with Th cells under Th2 (IL-4/anti-IL-12)
polarizing conditions (55.8 and 58.6%, respectively). To examine
whether the effects of vitD3 are limited to the BALB/c genetic
background or more generalized, we stimulated
CD4+Mel14+ T cells from
C57BL/6 mice with anti-CD3/anti-CD28 in the presence of vitD3.
As shown in Fig. 3B Th cells from C57BL/6 mice also develop
into highly polarized Th2 cells after single or multiple rounds of
stimulation. These findings clearly indicate that Th cells can be
direct targets for the effects of vitD3 on Th development as
demonstrated by significant induction of Th2 polarization in both
BALB/c and C57BL/6 mice.
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The enhanced vitD3-driven Th2 development was also abolished in
these APC-free cultures by neutralization of IL-4 (Fig. 4). However, neutralization of IL-4 also
led to an increase in the percentage of IFN--producing cells. Thus
it was possible that overproduction of IFN-, which can inhibit Th2
development (45), could be responsible for reduced numbers
of IL-4-producing cells, rather than a requirement for IL-4 in
vitD3-driven Th2 development. To exclude this possibility we
simultaneously neutralized both IL-4 and IFN- and assessed the
cytokine profile of naive CD4+ cells after
culture in the presence or absence of vitD3. Cells were repeatedly
stimulated with cross-linked anti-CD3 and soluble anti-CD28
mAb. As depicted in Fig. 4, when anti-IL-4 and anti-IFN- mAb
were added throughout the culture period of vitD3-driven cultures, the
cytokine profile of these vitD3 cultured cells resembled that of cells
cultured under neutral conditions (with no blocking mAb) with a low
frequency of IL-4-producing cells in vitD3-driven cultures when IL-4
and IFN- were absent. Taken together, these data clearly demonstrate
that the effects of vitD3 on the development of
CD4+ T cells are largely dependent on IL-4,
although small numbers of IL-4-producing cells can develop in the
complete absence of IL-4.
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In recent years considerable progress has been made in the
knowledge of transcription factors involved in Th1 and Th2 cell
differentiation. The transcription factor T-bet has been described to
direct the differentiation and commitment of Th1 cells, and to induce
IFN- expression (14). c-maf and GATA-3 are
Th2-specific transcription factors that regulate the Th2 cytokine genes
(8, 9, 10, 11, 12, 13). We examined whether vitD3 cultured Th cells
showed a transcription factor pattern reflecting the augmented Th2
development as indicate by their cytokine profile. As shown in Fig. 5 and in accordance with previously
published findings, highly polarized Th1 cells obtained after repeated
stimulation expressed T-bet, but low to undetectable levels of
c-maf and GATA-3. Conversely, Th2 cells expressed GATA-3 and
c-maf, but not T-bet. Naive
CD4+Mel14+ T cells
stimulated with anti-CD3 and anti-CD28 mAb in the presence of
vitD3 showed enhanced levels of GATA-3 and c-maf expression
as compared with cells grown under neutral conditions. No T-bet
expression was detected in cells cultured under neutral or vitD3-driven
conditions. These findings are representative of two independent
experiments. Therefore, the transcription factor profile
correlates with the increased Th2 cytokine production of
CD4+ cells cultured in the presence of vitD3.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
It has been suggested that the immunomodulatory effects of vitD3 are
mainly mediated via modulation of the activity of macrophages and
dendritic cells, via inhibition of their differentiation, maturation,
and T cell-stimulatory activity (30, 31, 46). More
specifically, reduced expression of costimulatory molecules (CD80,
CD86, CD58, and CD40) and inhibition of the production of cytokines,
like TNF-, IL-6, and IL-12, were shown to result in impaired T cell
activation (30). The inhibitory effect of vitD3 on
IL-12p70 production by DC via inhibition of NF-B activation and
transcriptional repression of the IL-12p40 gene (31) is
likely to play a dominant role in the observed reduction of Th1 cell
development after treatment with vitD3.
Although APC can be direct targets for the immunomodulatory activities of vitD3, we clearly show that vitD3 also has a direct effect on the differentiation of naive CD4+Mel14+ T cells upon TCR stimulation, resulting in inhibition of Th1 and augmented Th2 development. The vitD3 induced skewing toward a Th2 phenotype was much more pronounced when CD4+Mel14+ T cells were activated with anti-CD3/anti-CD28 mAb as compared with cells activated in the presence of APC and Ag. It is possible that APC may deliver signals to inhibit Th2 development, such as via IL-12 (31) or ICAM-1 (47, 48) which counteract the effects of vitD3. Additionally by its effect on downstream signaling pathways known to be triggered by TCR ligation, it is possible that vitD3 may modify the strength of the signal delivered to the T cell which has been shown to affect the development of Th1 and Th2 responses (49).
It has been reported that the transactivation of the IFN- promoter
is down-regulated by vitD3 in transfected Jurkat cells
(50). Thus, in our system, it is possible that
transcriptional suppression of the IFN- gene takes place, thereby
providing a possible explanation for the suppression of IFN-
production. This can be augmented by up-regulation of GATA-3 seen in
the presence of vitD3, because GATA-3 has been shown to inhibit the
development of IFN--producing cells early during Th cell
differentiation (11, 13). To date no vitD3 receptor
responsive elements in the IL-4 promoter have been described,
but the ability of vitD3 to up-regulate c-maf expression
could account for increased transactivation of the IL-4 promoter.
The vitD3 induced effects on Th development were largely mediated via
IL-4. However, a small population of IL-4-producing cells was detected
after culture in the presence of vitD3 in the presence of neutralizing
mAb to IFN- and IL-4. This IL-4-independent Th2 cell development may
be reminiscent of the findings by Ouyang et al. (51), who
showed STAT6-independent Th2 development.
We showed that Ag-specific stimulation of CD4+ T
cells in the presence of vitD3 inhibits the development of Th1 cells.
Conversely, we demonstrated the development of highly Th2 skewed
populations after in vitro culture with vitD3 with increased IL-4,
IL-5, and IL-10 production as determined by the intracellular cytokine
profile and immunoassay. The presence of vitD3 is required during each
phase of stimulation, because the developing Th2 cells are still
unstable until they are committed. Even Th cells cultured with
IL-12/anti-IL-4 mAb or IL-4/anti-IL-12 require these additives
until they are committed to the Th1 or Th2 phenotype, respectively
(7). Additionally, we provide data that vitD3 induced Th2
development can also be seen not only on the BALB/c but also on the
C57BL/6 genetic background. The vitD3 induced inhibition of Th1
development in APC/Ag stimulated cultures has been described before
(18, 33); therefore, our data confirm these findings.
However, the vitD3 induced increase of Th2 development has not been
demonstrated in vitro, and appears in apparent conflict with previous
studies where effects on Th2 development were minimal. In contrast to
other studies (18, 33), we used naive
CD4+ T cells and assessed the role of vitD3 in
the well-defined OVA-TCR transgenic system. Mattner et al.
(33) showed the effect of vitD3 on human cord blood
CD4+CD45RA+ T cells after
stimulation autologous adherent cells and PHA. After 10 days in culture
they found a reduction of IFN- production but only a mild increase
of IL-4. Differences may thus be explained by the different source of
naive T cells, and it is also possible that there is donor variation in
humans.
The physiological role of vitD3 in immune responses is still not
defined. Macrophages have been shown to synthesize vitD3 when activated
with LPS and IFN- (52) (data not shown). This implies
that upon triggering of APC by microbial factors vitD3 is synthesized
by these cells and thus may down-regulate the production of
inflammatory mediators, such as IL-12. This could initiate a cascade of
events resulting in reduced APC function and polarization of Th cells
toward Th2 dominated responses. The suppression of IFN- production
might prevent a sustained synthesis of vitD3, thereby providing a
negative feedback mechanism. Therefore, it is likely that vitD3
functions to dampen cell-mediated immune responses through prevention
of strong Th1 responses via the action on the APC, while simultaneously
directly acting on the T cell to enhance Th2 cell development. VitD3 is
also synthesized by keratinocytes after exposure of the skin to
ultraviolet B irradiation. Little is known about the role of locally
produced vitD3 in the skin. However, it is tempting to speculate that
vitD3 contributes to the immunomodulatory effects of ultraviolet B by
affecting the activity of APC and Th cells.
The dose of vitD3 used in our study was in the range of that used by others and did not induce apoptosis or strong inhibition of Th proliferation. Because macrophages, dendritic cells, and keratinocytes can produce vitD3 it is likely that at the localized level in vivo, high vitD3 can be found which may exert its effect on neighboring Th cells. For these reasons, however, it may be difficult to extrapolate from physiologically relevant concentrations of vitD3 in vivo to the in vitro system we are using.
In this study we have provided insight into the effect of vitD3 on Th polarization by showing for the first time that vitD3 is able to enhance Th2 development in the absence of APC. The potent direct effect of vitD3 on Th cells may, at least in part, explain its beneficial effects in the treatment of psoriatic lesions as well as a number of other autoimmune diseases. Augmented immune deviation into strong Th2 mediated responses by combined effects on APC and Th cells are likely to underlie the immunosuppressive activity of vitD3.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. André Boonstra, Department of Immunology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304. E-mail address: andre.boonstra{at}dnax.org
3 Abbreviation used in this paper: vitD3, 1,25-dihydroxyvitamin D3.
Received for publication April 23, 2001. Accepted for publication August 31, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Y. A. Taher, B. C. A. M. van Esch, G. A. Hofman, P. A. J. Henricks, and A. J. M. van Oosterhout 1{alpha},25-Dihydroxyvitamin D3 Potentiates the Beneficial Effects of Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-{beta} J. Immunol., April 15, 2008; 180(8): 5211 - 5221. [Abstract] [Full Text] [PDF]
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 C. P. Kovesdy, S. Ahmadzadeh, J. E. Anderson, and K. Kalantar-Zadeh Association of Activated Vitamin D Treatment and Mortality in Chronic Kidney Disease Arch Intern Med, February 25, 2008; 168(4): 397 - 403. [Abstract] [Full Text] [PDF]
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 M. Cutolo and K. Otsa Review: Vitamin D, immunity and lupus Lupus, January 1, 2008; 17(1): 6 - 10. [Abstract] [PDF]
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S. Gorman, L. A. Kuritzky, M. A. Judge, K. M. Dixon, J. P. McGlade, R. S. Mason, J. J. Finlay-Jones, and P. H. Hart Topically Applied 1,25-Dihydroxyvitamin D3 Enhances the Suppressive Activity of CD4+CD25+ Cells in the Draining Lymph Nodes J. Immunol., November 1, 2007; 179(9): 6273 - 6283. [Abstract] [Full Text] [PDF]
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 Y. Arnson, H. Amital, and Y. Shoenfeld Vitamin D and autoimmunity: new aetiological and therapeutic considerations Ann Rheum Dis, September 1, 2007; 66(9): 1137 - 1142. [Abstract] [Full Text] [PDF]
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S. Chen, G. P. Sims, X. X. Chen, Y. Y. Gu, S. Chen, and P. E. Lipsky Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation J. Immunol., August 1, 2007; 179(3): 1634 - 1647. [Abstract] [Full Text] [PDF]
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 G. E. Mullin and A. Dobs Vitamin D and Its Role in Cancer and Immunity: A Prescription for Sunlight Nutr Clin Pract, June 1, 2007; 22(3): 305 - 322. [Abstract] [Full Text] [PDF]
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 G. Devereux, A. A Litonjua, S. W Turner, L. C. Craig, G. McNeill, S. Martindale, P. J Helms, A. Seaton, and S. T Weiss Maternal vitamin D intake during pregnancy and early childhood wheezing Am. J. Clinical Nutrition, March 1, 2007; 85(3): 853 - 859. [Abstract] [Full Text] [PDF]
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J. Tian, Y. Liu, L. A. Williams, and D. de Zeeuw Potential role of active vitamin D in retarding the progression of chronic kidney disease Nephrol. Dial. Transplant., February 1, 2007; 22(2): 321 - 328. [Full Text] [PDF]
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 E. Baroni, M. Biffi, F. Benigni, A. Monno, D. Carlucci, G. Carmeliet, R. Bouillon, and D. D'Ambrosio VDR-dependent regulation of mast cell maturation mediated by 1,25-dihydroxyvitamin D3 J. Leukoc. Biol., January 1, 2007; 81(1): 250 - 262. [Abstract] [Full Text] [PDF]
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 K. N. Evans, L. Nguyen, J. Chan, B. A. Innes, J. N. Bulmer, M. D. Kilby, and M. Hewison Effects of 25-Hydroxyvitamin D3 and 1,25-Dihydroxyvitamin D3 on Cytokine Production by Human Decidual Cells Biol Reprod, December 1, 2006; 75(6): 816 - 822. [Abstract] [Full Text] [PDF]
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C. Daniel, H. H. Radeke, N. A. Sartory, N. Zahn, U. Zuegel, A. Steinmeyer, and J. Stein The New Low Calcemic Vitamin D Analog 22-Ene-25-Oxa-Vitamin D Prominently Ameliorates T Helper Cell Type 1-Mediated Colitis in Mice J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 622 - 631. [Abstract] [Full Text] [PDF]
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M. Li, P. Hener, Z. Zhang, S. Kato, D. Metzger, and P. Chambon Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis PNAS, August 1, 2006; 103(31): 11736 - 11741. [Abstract] [Full Text] [PDF]
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 J. Sun, J. Kong, Y. Duan, F. L. Szeto, A. Liao, J. L. Madara, and Y. C. Li Increased NF-{kappa}B activity in fibroblasts lacking the vitamin D receptor Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E315 - E322. [Abstract] [Full Text] [PDF]
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R. Grenningloh, A. Gho, P. di Lucia, M. Klaus, W. Bollag, I-C. Ho, F. Sinigaglia, and P. Panina-Bordignon Cutting Edge: Inhibition of the Retinoid X Receptor (RXR) Blocks T Helper 2 Differentiation and Prevents Allergic Lung Inflammation J. Immunol., May 1, 2006; 176(9): 5161 - 5166. [Abstract] [Full Text] [PDF]
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 Y.-J. Liu Thymic stromal lymphopoietin: master switch for allergic inflammation J. Exp. Med., February 21, 2006; 203(2): 269 - 273. [Abstract] [Full Text] [PDF]
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L. Chen, M. T. Cencioni, D. F. Angelini, G. Borsellino, L. Battistini, and C. F. Brosnan Transcriptional Profiling of {gamma}{delta} T Cells Identifies a Role for Vitamin D in the Immunoregulation of the V{gamma}9V{delta}2 Response to Phosphate-Containing Ligands J. Immunol., May 15, 2005; 174(10): 6144 - 6152. [Abstract] [Full Text] [PDF]
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 P.E. Norman and J.T. Powell Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 39 - 46. [Abstract] [Full Text] [PDF]
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 M. T. Cantorna and B. D. Mahon Mounting Evidence for Vitamin D as an Environmental Factor Affecting Autoimmune Disease Prevalence Experimental Biology and Medicine, December 1, 2004; 229(11): 1136 - 1142. [Abstract] [Full Text] [PDF]
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 A. H. Poon, C. Laprise, M. Lemire, A. Montpetit, D. Sinnett, E. Schurr, and T. J. Hudson Association of Vitamin D Receptor Genetic Variants with Susceptibility to Asthma and Atopy Am. J. Respir. Crit. Care Med., November 1, 2004; 170(9): 967 - 973. [Abstract] [Full Text] [PDF]
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A. Wittke, V. Weaver, B. D. Mahon, A. August, and M. T. Cantorna Vitamin D Receptor-Deficient Mice Fail to Develop Experimental Allergic Asthma J. Immunol., September 1, 2004; 173(5): 3432 - 3436. [Abstract] [Full Text] [PDF]
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 K. N. Evans, J. N. Bulmer, M. D. Kilby, and M. Hewison Vitamin D and Placental-Decidual Function Reproductive Sciences, July 1, 2004; 11(5): 263 - 271. [Abstract] [PDF]
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 S. G. Rhodes, L. A. Terry, J. Hope, R. G. Hewinson, and H. M. Vordermeier 1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle Clin. Vaccine Immunol., November 1, 2003; 10(6): 1129 - 1135. [Abstract] [Full Text] [PDF]
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M. Hewison, L. Freeman, S. V. Hughes, K. N. Evans, R. Bland, A. G. Eliopoulos, M. D. Kilby, P. A. H. Moss, and R. Chakraverty Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells J. Immunol., June 1, 2003; 170(11): 5382 - 5390. [Abstract] [Full Text] [PDF]
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A. Gurlek, M. R. Pittelkow, and R. Kumar Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1{alpha},25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation Endocr. Rev., December 1, 2002; 23(6): 763 - 786. [Abstract] [Full Text] [PDF]
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 A. G.S. van Halteren, E. van Etten, E. C. de Jong, R. Bouillon, B. O. Roep, and C. Mathieu Redirection of Human Autoreactive T-Cells Upon Interaction With Dendritic Cells Modulated by TX527, an Analog of 1,25 Dihydroxyvitamin D3 Diabetes, July 1, 2002; 51(7): 2119 - 2125. [Abstract] [Full Text] [PDF]
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C. B. Stephensen, R. Rasooly, X. Jiang, M. A. Ceddia, C. T. Weaver, R. A. S. Chandraratna, and R. P. Bucy Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway J. Immunol., May 1, 2002; 168(9): 4495 - 4503. [Abstract] [Full Text] [PDF]
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T. P. Staeva-Vieira and L. P. Freedman 1,25-Dihydroxyvitamin D3 Inhibits IFN-{gamma} and IL-4 Levels During In Vitro Polarization of Primary Murine CD4+ T Cells J. Immunol., February 1, 2002; 168(3): 1181 - 1189. [Abstract] [Full Text] [PDF]
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