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PD-L1 expression on tolerogenic APCs is controlled by STAT-3

During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14+ monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others ch...

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Main Authors: Wölfle, Sabine J. (Author) , Strebovsky, Julia (Author) , Bartz, Holger (Author) , Sähr, Aline (Author) , Arnold, Caroline (Author) , Kaiser, Claus (Author) , Dalpke, Alexander (Author) , Heeg, Klaus (Author)
Format: Article (Journal)
Language:English
Published: 2011
In: European journal of immunology
Year: 2011, Volume: 41, Issue: 2, Pages: 413-424
ISSN:1521-4141
DOI:10.1002/eji.201040979
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/eji.201040979
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/eji.201040979
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Author Notes:Sabine J. Wölfle, Julia Strebovsky, Holger Bartz, Aline Sähr, Caroline Arnold, Claus Kaiser, Alexander H. Dalpke and Klaus Heeg
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Summary:During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14+ monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others characterized these APCs (TLR-APC) by a retained expression of CD14 and a lack of CD1a. Here, we show in addition, expression of programmed death ligand-1 (PD-L1). TLR-APCs failed to induce T-cell proliferation and furthermore were able to induce CD25+Foxp3+ T regulatory cells (Tregs). Since PD-L1 is described as a key negative regulator and inducer of tolerance, we further analyzed its regulation. PD-L1 expression was regulated in a MAPK/cytokine/STAT-3-dependent manner: high levels of IL-6 and IL-10 that signal via STAT-3 were produced by TLR-APCs. Blocking of STAT-3 activation prevented PD-L1 expression. Moreover, chromatin immunoprecipitation revealed direct binding of STAT-3 to the PD-L1 promoter. Those findings indicate a pivotal role of STAT-3 in regulating PD-L1 expression. MAPKs were indirectly engaged, as blocking of p38 and p44/42 MAPKs decreased IL-6 and IL-10 thus reducing STAT-3 activation and subsequent PD-L1 expression. Hence, during DC differentiation TLR agonists induce a STAT-3-mediated expression of PD-L1 and favor the development of tolerogenic APCs.
Item Description:First published: 08 December 2010
Gesehen am 05.12.2022
Physical Description:Online Resource
ISSN:1521-4141
DOI:10.1002/eji.201040979

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