All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation

Benson, Micah J.; Pino‐Lagos, Karina; Rosemblatt, Mario; Noelle, Randolph J.

doi:10.1084/jem.20070719

Cited by 750 publications

(721 citation statements)

References 28 publications

(39 reference statements)

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“…Less than 15% of the iTreg had reverted in vivo 8 and 14 days after transfer into untreated syngeneic mice (Fig. 2E) confirming previously published results [14,19]. In contrast, Foxp3 expression of the transferred iTreg was not stable after transfer to irradiated hosts (Fig.…”

Section: Resultssupporting

confidence: 90%

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Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

et al. 2009

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Induced antigen-specific Foxp3 1 T cells (iTreg) are being discussed as a promising alternative to polyclonal natural Foxp3 1 T cells (nTreg) for cell-based therapies, particularly to achieve transplantation tolerance. Using Foxp3eGFP-reporter mice, we here establish an efficient protocol to induce and expand alloantigen-specific iTreg from Foxp3 À CD4 1 T cells with cluster-disrupted DC. These iTreg were mainly CD62L 1 and showed efficient suppressive activity in vitro. However, in contrast to nTreg, adoptively transferred iTreg entirely failed to prevent lethal graft versus host disease (GVHD). Within irradiated recipients, the majority of adoptively transferred Foxp3 1 iTreg, but not Foxp3 1 nTreg quickly reverted to Foxp3 À CD4 1 T cells. We therefore suggest that therapeutic approaches to treat GVHD should rely on nTreg, whereas the use of de novo alloantigen-induced iTreg should be handled with caution since the stability of the regulatory phenotype of the iTreg could be of major concern.Key words: Animal models . Dendritic cells . Graft rejection . Regulatory T cells See accompanying article by commentary by Edinger IntroductionRecent advances have demonstrated that adoptively transferred exogenous Treg can inhibit graft versus host disease (GVHD) [1][2][3]. However, the availability of sufficient numbers of donor Treg for cell-based therapies remains limited [4]. Besides the in vitro expansion of nTreg [5], an obvious approach to solve this problem would be the de novo induction and expansion of Foxp3 1 Treg from abundant naïve CD4 1 T cells with recipient alloantigens [6,7]. Instead of mediating unspecific suppression, such alloantigen-induced Treg potentially could provide the advantage of antigen-specific regulation, thereby reducing the risk of disease relapse and infections [8]. Here, we present an efficient protocol to induce Foxp3 1 Treg by the use of clusterdisrupted allogeneic DC. Such allo DC-induced iTreg were functionally active in vitro and displayed a stable regulatory phenotype upon adoptive transfer into untreated syngeneic recipients. However, when used in experimental acute GVHD, these cells quickly lost Foxp3 expression and, in contrast to nTreg, did not show any protective effect. SHORT COMMUNICATION Results and discussionTo define conditions suited for the de novo induction of alloantigen-specific iTreg, we isolated Foxp3 À CD4 1 T cells from C57BL/6 Foxp3EGFP mice and co-cultured them with BM-derived allogeneic BALB/c DC that were either matured by application of LPS or via ''cluster-disruption'' (CD-DC). Disruption of the Ecadherin-mediated cell-cell contacts induces DC maturation through mechanisms distinct from TLR signaling [9]. Since antigen-loaded CD-DC have been shown to induce tolerance in mice after i.v. injection [9] we established a protocol that allowed the conversion of naïve to Foxp3 expressing cells in vitro in the presence of allogeneic but not syngeneic CD-DC. When compared with LPS-matured DC, CD-DC showed equally high expression of MHC class II, but diminished up...

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Section: Resultssupporting

confidence: 90%

“…The co-culture of purified Foxp3 À CD4 1 T cells with CD-DC under conditions supporting the generation of iTreg, i.e. with TGF-b [10, 11], IL-2 [12] and retinoic acid (RA) [13,14], induced expression of Foxp3 in approximately $12% of CD4 1 T cells (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

et al. 2009

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“…The upregulation of surface expression of galectin-3 is particularly interesting given the recent observation that galectin-3, recruited intracellularly to the immunological synapse, negatively regulates TCR-mediated CD4 1 T-cell activation [28]. Generation of Treg has been associated with suboptimal T-cell activation, resulting from antigen presentation by immature or sub-optimally primed DC [29,30]. The ability of galectin-3 to influence the immunological synapse together with the ability of SEA to modulate DC maturation may play a key role in favoring the development of Foxp3-expressing cells in our T-cell/DC co-cultures [25].…”

Section: Discussionmentioning

confidence: 99%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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The immunomodulatory effect of Schistosoma mansoni antigens has often been attributed to interaction with PRR expressed on APC. Our previous work has shown that S. mansonisoluble egg antigen (SEA) can induce, together with a Th2 response, TGF-b-dependent Foxp3 expression in naïve CD4 1 T cells from NOD mice. We found that SEA can directly upregulate the expression of surface-bound TGF-b in purified CD4 1 T cells in the absence of accessory cell interactions. In this study, we show that the C-type lectin receptors DEC-205 and galectin-3 were involved in the direct interaction between S. mansoni antigens and CD4 1 T cells. SEA was able to enhance CD4 1 T-cell secretion of bioactive TGF-b in response to TLR2 ligand stimulation, in the absence of APC. We also show that TLR2 expressed on CD4 1 T cells was important for the Foxp3 expression induced by SEA.

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“…Dietary components likely also influence the development of the mucosal immune system in many ways, including stabilization of the microbiota. RA, a metabolite of dietary component vitamin A, has been shown to educate the mucosal DC to imprint primed T cells and B cells with gut tropism [21][22][23][24]. Recent reports further demonstrated that intestine is enriched for DC expressing RA metabolizing enzyme ALDH1a and that RA is a key regulator of TGF-b dependent immune responses by promoting Treg differentiation and inhibiting Th17 cell development [9,11].…”

Section: Introductionmentioning

confidence: 99%

Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine‐protective regulatory T cells

Cong¹,

Wang²,

Konrad³

et al. 2009

Eur J Immunol

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The gut is home to a large number of Treg, with both CD4 1 CD25 1 Treg and bacterial antigen-specific Tr1 cells present in normal mouse intestinal lamina propria. It has been shown recently that intestinal mucosal DC are able to induce Foxp3 1 Treg through production of TGF-b plus retinoic acid (RA). However, the factors instructing DC toward this mucosal phenotype are currently unknown. Curcumin has been shown to possess a number of biologic activities including the inhibition of NF-jB signaling. We asked whether curcumin could modulate DC to be tolerogenic whose function could mimic mucosal DC. We report here that curcumin modulated BM-derived DC to express ALDH1a and IL-10. These curcumin-treated DC induced differentiation of naïve CD4 1 T cells into Treg resembling Treg in the intestine, including both CD4 1 CD25 1 Foxp3 1 Treg and IL-10-producing Tr1 cells. Such Treg induction required IL-10, TGF-b and retinoic acid produced by curcumin-modulated DC. Cell contact as well as IL-10 and TGF-b production were involved in the function of such induced Treg. More importantly, these Treg inhibited antigen-specific T-cell activation in vitro and inhibited colitis due to antigen-specific pathogenic T cells in vivo.

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All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation

Cited by 750 publications

References 28 publications

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine‐protective regulatory T cells

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All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation

Cited by 750 publications

References 28 publications

Alloantigen‐specific de novo‐induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD

Alloantigen‐specific de novo‐induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine‐protective regulatory T cells

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Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD