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

Autor: Caroline Arnold, Klaus Heeg, Julia Strebovsky, Aline Sahr, Holger Bartz, Claus Kaiser, Alexander H. Dalpke, Sabine J. Wölfle
Rok vydání: 2011
Předmět:
STAT3 Transcription Factor
medicine.medical_treatment
CD14
Immunology
Lipopolysaccharide Receptors
Antigen-Presenting Cells
Biology
T-Lymphocytes
Regulatory
p38 Mitogen-Activated Protein Kinases
B7-H1 Antigen
Monocytes
Antigens
CD1
Antigens
CD
T-Lymphocyte Subsets
PD-L1
Immune Tolerance
medicine
Humans
Immunology and Allergy
IL-2 receptor
Phosphorylation
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Innate immune system
Interleukin-6
Toll-Like Receptors
Histocompatibility Antigens Class II
Imidazoles
Granulocyte-Macrophage Colony-Stimulating Factor
FOXP3
Cell Differentiation
Dendritic Cells
Interleukin-10
Cell biology
STAT Transcription Factors
Cytokine
Gene Expression Regulation
biology.protein
Interleukin-4
Lymphocyte Culture Test
Mixed
Chromatin immunoprecipitation
Signal Transduction
Zdroj: European Journal of Immunology. 41:413-424
ISSN: 0014-2980
DOI: 10.1002/eji.201040979
Popis: 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.
Databáze: OpenAIRE
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