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

Eur J Immunol. 2011 Feb;41(2):413-24. doi: 10.1002/eji.201040979. Epub 2011 Jan 11.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / metabolism*
  • Antigens, CD / metabolism*
  • Antigens, CD1 / metabolism
  • B7-H1 Antigen
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Gene Expression Regulation / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Imidazoles / pharmacology
  • Immune Tolerance / physiology*
  • Interleukin-10 / metabolism
  • Interleukin-4 / pharmacology
  • Interleukin-6 / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Lymphocyte Culture Test, Mixed
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / immunology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • STAT Transcription Factors / antagonists & inhibitors
  • STAT Transcription Factors / metabolism
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Toll-Like Receptors / agonists
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antigens, CD
  • Antigens, CD1
  • B7-H1 Antigen
  • CD1a antigen
  • CD274 protein, human
  • Histocompatibility Antigens Class II
  • IL10 protein, human
  • IL6 protein, human
  • Imidazoles
  • Interleukin-6
  • Lipopolysaccharide Receptors
  • Protein Kinase Inhibitors
  • STAT Transcription Factors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Toll-Like Receptors
  • Interleukin-10
  • Interleukin-4
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • resiquimod