Vitamin A and the immune system of the gut

[Guest guest]

Dear All,

At the last conference (Denver in May 2007), I asked a question about

the role of vitamin A in regulating the balance of inflammatory T

helper (Th) cells versus anti-inflammatory regulatory T cells (Tregs)

in IBD. A lot of evidence suggests that dietary carotenoids

(carotenes) are metabolized to vitamin A in the gut-associated

lymphoid tissues. Vitamin A deficiency is common in IBD and PSC. This

recent paper confirms that vitamin A metabolites induce a set of

Tregs that have special " gut-homing " properties:

________________

J. Immunol. 2007 Sep 15;179(6):3724-33.

Vitamin A Metabolites Induce Gut-Homing FoxP3+ Regulatory T Cells.

Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH

Laboratory of Immunology and Hematopoiesis, Department of Comparative

Pathobiology and.

In this study, we report a novel biological function of vitamin A

metabolites in conversion of naive FoxP3(-) CD4(+) T cells into a

unique FoxP3(+) regulatory T cell subset (termed " retinoid-induced

FoxP3(+) T cells " ) in both human and mouse T cells. We found that the

major vitamin A metabolite all-trans-retinoic acid induces histone

acetylation at the FoxP3 gene promoter and expression of the FoxP3

protein in CD4(+) T cells. The induction of retinoid-induced FoxP3(+)

T cells is mediated by the nuclear retinoic acid receptor alpha and

involves T cell activation driven by mucosal dendritic cells and

costimulation through CD28. Retinoic acid can promote TGF-beta1-

dependent generation of FoxP3(+) regulatory T cells but decrease the

TGF-beta1- and IL-6-dependent generation of inflammatory Th17 cells

in mouse T cells. Retinoid-induced FoxP3(+) T cells can efficiently

suppress target cells and, thus, have a regulatory function typical

for FoxP3(+) T cells. A unique cellular feature of these regulatory T

cells is their high expression of gut-homing receptors that are

important for migration to the mucosal tissues particularly the small

intestine. Taken together, these results identify retinoids as

positive regulatory factors for generation of gut-homing FoxP3(+) T

cells. PMID: 17785809.

________________

This also fits with recent evidence that the vitamin A metabolite,

retinoic acid, controls a " switch " between inflammatory Th17 cells

and anti-inflammatory Tregs:

________________

Science. 2007 Jul 13;317(5835):256-60.

Reciprocal TH17 and regulatory T cell differentiation mediated by

retinoic acid.

Mucida D, Park Y, Kim G, Turovskaya O, I, Kronenberg M,

Cheroutre H

La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La

Jolla, CA 92037, USA.

The cytokine transforming growth factor-beta (TGF-beta) converts

naïve T cells into regulatory T (Treg) cells that prevent

autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-

beta has also been found to promote the differentiation of naïve T

lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17

(T(H)17) cells, which promote autoimmunity and inflammation. This

raises the question of how TGF-beta can generate such distinct

outcomes. We identified the vitamin A metabolite retinoic acid as a

key regulator of TGF-beta-dependent immune responses, capable of

inhibiting the IL-6-driven induction of proinflammatory T(H)17 cells

and promoting anti-inflammatory Treg cell differentiation. These

findings indicate that a common metabolite can regulate the balance

between pro- and anti-inflammatory immunity. PMID: 17569825.

_________________

Eur J Immunol. 2007 Sep;37(9):2396-9.

Activation of retinoic acid receptor-alpha favours regulatory T cell

induction at the expense of IL-17-secreting T helper cell

differentiation.

Schambach F, Schupp M, Lazar MA, Reiner SL

Abramson Family Cancer Research Institute and Department of Medicine,

University of Pennsylvania, USA.

Autoimmunity is thought to reflect an imbalance between regulatory T

helper lymphocytes (Treg) and pathogenic, IL-17-secreting T helper

(Th17) cells. Induction of both adaptive Treg and Th17 cells requires

signalling from TGF-beta. We now show that, in the context of TGF-

beta signalling, all-trans retinoic acid (ATRA) leads to increased

induction of CD4(+) T cells expressing the Treg specification factor

forkhead box protein P3 (FoxP3) and decreased frequency of cells

expressing IL-17, even in the presence of IL-6. Using a specific

agonist and antagonist, as well as retroviral over-expression, we

also provide evidence that the effects of ATRA are likely to be at

least partially mediated by the nuclear retinoic acid receptor-alpha

(RARalpha). These findings indicate that signalling through a

specific nuclear retinoic acid receptor can favour the decision to

adopt the Treg fate at the expense of Th17 fate. Specific agonists of

RARalpha could, therefore, be considered candidates for the treatment

of autoimmunity. PMID: 17694576.

______________

It's interesting that this line of evidence converges with the

regulation of the pregnane X receptor (PXR) mentioned in my previous

post. PXR forms a dimer with the retinoid X receptor (RXR), and the

latter is activated by 9-cis-retinoic acid [derived from vitamin A]

(and/or docosahexaenoic acid), as discussed in the December 2006

issue of our newsletter.

I wouldn't be surprised if it is eventually found that vitamin A

deficiency may be one of the environmental factors pre-disposing to

IBD and/or PSC.

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Keep asking those questions Dave !Only as we keep asking questions can we get the answers we need.Very interesting.LeeDear All,At the last conference (Denver in May 2007), I asked a question about the role of vitamin A in regulating the balance of inflammatory T helper (Th) cells versus anti-inflammatory regulatory T cells (Tregs) in IBD. A lot of evidence suggests that dietary carotenoids (carotenes) are metabolized to vitamin A in the gut-associated lymphoid tissues. Vitamin A deficiency is common in IBD and PSC. This recent paper confirms that vitamin A metabolites induce a set of Tregs that have special "gut-homing" properties:________________J. Immunol. 2007 Sep 15;179(6):3724-33. Vitamin A Metabolites Induce Gut-Homing FoxP3+ Regulatory T Cells.Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CHLaboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology and.In this study, we report a novel biological function of vitamin A metabolites in conversion of naive FoxP3(-) CD4(+) T cells into a unique FoxP3(+) regulatory T cell subset (termed "retinoid-induced FoxP3(+) T cells") in both human and mouse T cells. We found that the major vitamin A metabolite all-trans-retinoic acid induces histone acetylation at the FoxP3 gene promoter and expression of the FoxP3 protein in CD4(+) T cells. The induction of retinoid-induced FoxP3(+) T cells is mediated by the nuclear retinoic acid receptor alpha and involves T cell activation driven by mucosal dendritic cells and costimulation through CD28. Retinoic acid can promote TGF-beta1-dependent generation of FoxP3(+) regulatory T cells but decrease the TGF-beta1- and IL-6-dependent generation of inflammatory Th17 cells in mouse T cells. Retinoid-induced FoxP3(+) T cells can efficiently suppress target cells and, thus, have a regulatory function typical for FoxP3(+) T cells. A unique cellular feature of these regulatory T cells is their high expression of gut-homing receptors that are important for migration to the mucosal tissues particularly the small intestine. Taken together, these results identify retinoids as positive regulatory factors for generation of gut-homing FoxP3(+) T cells. PMID: 17785809.________________This also fits with recent evidence that the vitamin A metabolite, retinoic acid, controls a "switch" between inflammatory Th17 cells and anti-inflammatory Tregs:________________Science. 2007 Jul 13;317(5835):256-60.Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.Mucida D, Park Y, Kim G, Turovskaya O, I, Kronenberg M, Cheroutre HLa Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.The cytokine transforming growth factor-beta (TGF-beta) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-beta has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T(H)17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory T(H)17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity. PMID: 17569825._________________Eur J Immunol. 2007 Sep;37(9):2396-9.Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation.Schambach F, Schupp M, Lazar MA, Reiner SLAbramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, USA.Autoimmunity is thought to reflect an imbalance between regulatory T helper lymphocytes (Treg) and pathogenic, IL-17-secreting T helper (Th17) cells. Induction of both adaptive Treg and Th17 cells requires signalling from TGF-beta. We now show that, in the context of TGF-beta signalling, all-trans retinoic acid (ATRA) leads to increased induction of CD4(+) T cells expressing the Treg specification factor forkhead box protein P3 (FoxP3) and decreased frequency of cells expressing IL-17, even in the presence of IL-6. Using a specific agonist and antagonist, as well as retroviral over-expression, we also provide evidence that the effects of ATRA are likely to be at least partially mediated by the nuclear retinoic acid receptor-alpha (RARalpha). These findings indicate that signalling through a specific nuclear retinoic acid receptor can favour the decision to adopt the Treg fate at the expense of Th17 fate. Specific agonists of RARalpha could, therefore, be considered candidates for the treatment of autoimmunity. PMID: 17694576.______________It's interesting that this line of evidence converges with the regulation of the pregnane X receptor (PXR) mentioned in my previous post. PXR forms a dimer with the retinoid X receptor (RXR), and the latter is activated by 9-cis-retinoic acid [derived from vitamin A] (and/or docosahexaenoic acid), as discussed in the December 2006 issue of our newsletter.I wouldn't be surprised if it is eventually found that vitamin A deficiency may be one of the environmental factors pre-disposing to IBD and/or PSC. Dave (father of (22); PSC 07/03; UC 08/03)