Thymic Stromal Lymphopoietin-Activated Plasmacytoid Dendritic Cells Induce the Generation of FOXP3+ Regulatory T Cells in Human Thymus

Hanabuchi, Shino; Ito, Tomoki; Park, Woon Ryon; Watanabe, Norihiko; Shaw, Joanne; Román, Eulogia; Arima, Kazuhiko; Wang, Yui Hsi; Voo, Kui Shin; Cao, Wei; Liu, Yong Jun

doi:10.4049/jimmunol.0804106

Cited by 184 publications

(145 citation statements)

References 43 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…The observation that synthesis of TGF-b was enhanced in pancreatic Tregs recruited by CCL22-producing splenic CD8a 2 mDCs, although IL-10 was not detected (Fig. 3D), is in accordance with the report that human CD8a 2 mDCs are able to synthesize CCL22 upon activation with thymic stromal lymphopoietin, promoting the accumulation of TGF-b + rather than IL-10 + Tregs (17). CCL22 attracts CCR4-expressing T cells that include activated memory T cells and Tregs, the latter expressing high levels of the chemokine receptor CCR4 (15).…”

Section: Cd8asupporting

confidence: 79%

CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

Layseca-Espinosa

Korniotis

Montandon

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

G-CSF prevents type 1 diabetes in the NOD mouse by promoting the local recruitment of T regulatory cells (Tregs). This is an indirect effect because adoptive transfer of G-CSF–induced tolerogenic dendritic cells (DCs) promotes Treg accumulation. However, the identity of the particular DC subset and the molecule(s) mediating this effect remain unknown. We demonstrate in this study that the adoptive transfer of CD11chighCD8α− DCs isolated from pegylated G-CSF (pegG-CSF) recipients, but not that of other DC subtypes, enhanced the pancreatic recruitment of CD4+CD25+Foxp3+ Tregs, which generated increased amounts of TGF-β. Likewise, only CD11chighCD8α− DCs from pegG-CSF recipients secreted the chemokine CCL22 at levels that effectively attracted Tregs. PegG-CSF was more efficient at enhancing the synthesis of CCL22 by CD11chighCD8α− DCs from the pancreatic lymph nodes compared with those from the spleen. Accordingly, CD11chighCD8α− DCs from the pancreatic lymph nodes of pegG-CSF recipients were more efficient than their splenic counterparts in the recruitment of Tregs upon adoptive transfer. Predictably, CD11chighCD8α− DCs failed to recruit these Tregs both in vivo and in vitro following intracellular neutralization of CCL22. These data assign a key role to CD8α− DCs and CCL22 in Treg recruitment in the protection of NOD mice against type 1 diabetes following the treatment with G-CSF.

show abstract

Section: Cd8asupporting

confidence: 79%

CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

Layseca-Espinosa

Korniotis

Montandon

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In agreement, it was recently suggested that human Treg-cell progenitors may selectively reside within mature DP thymocytes expressing high levels of CD69 and TCR-ab, since these cells develop into CD4SP Treg cells in response to activated autologous plasmacytoid and myeloid DCs [40], although not excluding the possibility of FOXP3 induction at the SP stages [41,42]. Additionally, our multiple regression analyses show a significant statistical dependency of the FOXP3 1 DP and SP populations, further supporting their direct precursor-product association.…”

Section: Discussionmentioning

confidence: 79%

Differentiation of human thymic regulatory T cells at the double positive stage

et al. 2011

View full text Add to dashboard Cite

Treg cells, best identified by the expression of the transcription factor FOXP3, play a crucial role in maintaining self-tolerance. Natural Treg cells constitute an independent thymusderived T-cell lineage whose developmental program in humans is still ill-defined. Here, we provide evidence of a Treg-cell differentiation pathway at the double positive (DP) stage, prior to commitment to the CD4 1 or CD8 1 lineage, in pediatric thymuses. FOXP3 1 DP cells displayed a functional IL-7 receptor and increased Bcl-2 levels that may protect them from cell death/negative selection, and an activated/suppressive phenotype that was lost as CD4 single positive (SP) cells matured and acquired egress markers. A subpopulation of FOXP3 1 DP thymocytes expressing CD103 likely represents the precursor of FOXP3 1 CD8SP cells, which homogeneously expressed this mucosal-homing molecule. Finally, co-cultures of DP thymocytes with primary thymic epithelial cells and multiple linear regression analyses support that FOXP3 1 SP cells are largely derived from FOXP3 1 DP thymocytes. Overall, our data suggest that human Treg-cell lineage commitment significantly occurs at the DP stage with possible implications for the diversity and autoreactivity of the natural Treg-cell repertoire.Key words: FOXP3 . Human T-cell development . Treg cells . Thymus Supporting Information available online IntroductionThe thymus is essential for the establishment and renewal of the peripheral T-cell compartment with a diverse repertoire, able to efficiently respond to novel pathogens, yet tolerant to selfantigens. Tolerance is at least partly achieved through the thymic production of a subset of T cells termed ''natural'' Treg cells. Treg cells modulate the activation and function of other T cells, as well as of other cell populations of the immune system, playing important roles not only in the prevention of autoimmune diseases, but also in other clinical settings, such as tumor immunity and persistent infections [1,2]. Currently, the forkhead/winged-helix transcription factor FOXP3 is considered as the best available marker to identify Treg cells. The essential role of FOXP3 in human Treg-cell development and function is attested by the association of FOXP3 defects with the fatal condition IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome [3]. Although understanding Treg-cell development in the human thymus is critical for their manipulation [4], the developmental program that Treg-cell precursors undergo to give rise to mature FOXP3 1 cells is still unclear. 3604T-cell development proceeds through a series of stages that can be tracked by the expression of CD3, CD4 and CD8. In humans, CD4 -CD8 -CD3 -triple negative cells first acquire CD4 (CD4 1 immature single positive) and then CD8 to become CD4 1 CD8 1 (double positive, DP) cells. DP cells bearing TCR-ab complexes able to engage self-MHC molecules are signaled to survive (positive selection) and to differentiate into functionally mature CD4 1 single positive (CD4SP; CD4 1 CD8...

show abstract

“…This further supported the role of pDC such as a cellular source of TGF-b, like TGF-b-producing Tregs (32,34), to polarize Th17 cells. In contrast, human thymic pDC have been involved in Treg induction when stimulated by the thymic stromal lymphopoietin produced by the thymic epithelial cells (39). Therefore, depending on the microenvironment, pDC might be a key player in TGF-b-dependent T cell commitment such as Tregs and Th17 cells.…”

Section: Discussionmentioning

confidence: 92%

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

TGF-β is required for both Foxp3+ regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-β on pDC, and to our knowledge, no study has assessed the capacity of TGF-β–exposed pDC to polarize naive CD4+ T cells. In this paper, we show that TGF-β–treated pDC favor Th17 but not Treg commitment. This process involves a TGF-β/Smad signal, because TGF-β treatment induced Smad2 phosphorylation in pDC and blockade of TGF-β signaling with the SD208 TGF-βRI kinase inhibitor abrogated Th17 commitment induced by TGF-β–treated pDC. Moreover, TGF-β mRNA synthesis and active TGF-β release were induced in TGF-β–treated pDC and anti–TGF-β Ab blocked Th17 commitment. Unexpectedly, TGF-β treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-β–exposed pDC, because elimination of IL-6–mediated signal with either IL-6– or IL-6Rα–specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-β–treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-β–treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-β–rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens.

show abstract

Thymic Stromal Lymphopoietin-Activated Plasmacytoid Dendritic Cells Induce the Generation of FOXP3+ Regulatory T Cells in Human Thymus

Cited by 184 publications

References 43 publications

CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

Differentiation of human thymic regulatory T cells at the double positive stage

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Contact Info

Product

Resources

About