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Closed Access item Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

Authors:Martín-Gayo, Enrique
Sierra-Filardi, Elena
Corbí, Angel L.
Toribio, María Luisa
Issue Date:31-Mar-2010
Publisher:American Society of Hematology
Citation:Blood 115:5366-5375 (2010)
Abstract:The generation of natural regulatory T cells (nTregs) is crucial for the establishment of immunological self-tolerance and the prevention of autoimmunity. Still, the origin of nTregs and the mechanisms governing their differentiation within the thymus are poorly understood, particularly in humans. It was recently shown that conventional dendritic cells (cDCs) in human thymus were capable of inducing nTreg differentiation. However, the function of plasmacytoid DCs (pDCs), the other major subset of thymic DCs, remains unknown. Here we report that pDCs resident in the human thymus, when activated with CD40L plus IL-3, efficiently promoted the generation of CD4+CD25+Foxp3+ nTregs from autologous thymocytes. The progenitors of these nTregs were selectively found within CD4+CD8+ thymocytes that had accomplished positive selection, as judged by their CD69hi TCRhi phenotype. Supporting the involvement of the CD40-CD40L pathway in pDC-induced nTreg generation, we show that positively-selected CD4+CD8+ progenitors specifically transcribed CD40L in vivo and up-regulated CD40L expression upon TCR engagement, thereby promoting the activation of pDCs. Finally, evidence is provided that nTregs primed by pDCs displayed reciprocal IL-10/TGFβ cytokine expression profiles as compared with nTregs primed by cDCs. This functional diversity further supports a non-redundant tolerogenic role for thymic pDCs in the human thymus.
Description:PMID: 20357241 [PubMed].-- Blood First Edition Paper, prepublished online March 31, 2010.
Publisher version (URL):http://dx.doi.org/10.1182/blood-2009-10-248260
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