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PD-L1 expression on tolerogenic APCs is controlled by STAT-3.
Eur J Immunol. 2011 Feb; 41(2):413-24.EJ

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.

Authors+Show Affiliations

Department for Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21268011

Citation

Wölfle, Sabine J., et al. "PD-L1 Expression On Tolerogenic APCs Is Controlled By STAT-3." European Journal of Immunology, vol. 41, no. 2, 2011, pp. 413-24.
Wölfle SJ, Strebovsky J, Bartz H, et al. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol. 2011;41(2):413-24.
Wölfle, S. J., Strebovsky, J., Bartz, H., Sähr, A., Arnold, C., Kaiser, C., Dalpke, A. H., & Heeg, K. (2011). PD-L1 expression on tolerogenic APCs is controlled by STAT-3. European Journal of Immunology, 41(2), 413-24. https://doi.org/10.1002/eji.201040979
Wölfle SJ, et al. PD-L1 Expression On Tolerogenic APCs Is Controlled By STAT-3. Eur J Immunol. 2011;41(2):413-24. PubMed PMID: 21268011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PD-L1 expression on tolerogenic APCs is controlled by STAT-3. AU - Wölfle,Sabine J, AU - Strebovsky,Julia, AU - Bartz,Holger, AU - Sähr,Aline, AU - Arnold,Caroline, AU - Kaiser,Claus, AU - Dalpke,Alexander H, AU - Heeg,Klaus, Y1 - 2011/01/11/ PY - 2010/08/24/received PY - 2010/11/04/revised PY - 2010/11/25/accepted PY - 2011/1/27/entrez PY - 2011/1/27/pubmed PY - 2011/4/6/medline SP - 413 EP - 24 JF - European journal of immunology JO - Eur J Immunol VL - 41 IS - 2 N2 - 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. SN - 1521-4141 UR - https://www.unboundmedicine.com/medline/citation/21268011/PD_L1_expression_on_tolerogenic_APCs_is_controlled_by_STAT_3_ L2 - https://doi.org/10.1002/eji.201040979 DB - PRIME DP - Unbound Medicine ER -