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 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.
Department for Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Germany.
Sabine J
SJ
Wölfle
Julia
J
Strebovsky
Holger
H
Bartz
Aline
A
Sähr
Caroline
C
Arnold
Claus
C
Kaiser
Alexander H
AH
Dalpke
Klaus
K
Heeg
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D015703:Antigens, CD; D018949:Antigens, CD1; D060890:B7-H1 Antigen; C419393:CD1a antigen; C423236:CD274 protein, human; D000949:Histocompatibility Antigens Class II; C508609:IL10 protein, human; C508600:IL6 protein, human; D007093:Imidazoles; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051193:Toll-Like Receptors; D016753:Interleukin-10; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C402365:resiquimod