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B7-H1-deficiency enhances the potential of tolerogenic dendritic cells by activating CD1d-restricted type II NKT cells.

Brandl C, Ortler S, Herrmann T, Cardell S, Lutz MB, Wiendl H - PLoS ONE (2010)

Bottom Line: Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC.Injections of B7-H1(-/-) TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-gamma production in the CNS.In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4(+) and NKT cell responses is enhanced.

View Article: PubMed Central - PubMed

Affiliation: Institute of Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.

ABSTRACT

Background: Dendritic cells (DC) can act tolerogenic at a semi-mature stage by induction of protective CD4(+) T cell and NKT cell responses.

Methodology/principal findings: Here we studied the role of the co-inhibitory molecule B7-H1 (PD-L1, CD274) on semi-mature DC that were generated from bone marrow (BM) cells of B7-H1(-/-) mice and applied to the model of Experimental Autoimmune Encephalomyelitis (EAE). Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC. Injections of B7-H1(-/-) TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-gamma production in the CNS. Experiments in CD1d(-/-) and Jalpha281(-/-) mice as well as with type I and II NKT cell lines indicated that only type II NKT cells but not type I NKT cells (invariant NKT cells) could be stimulated by an endogenous CD1d-ligand on DC and were responsible for the increased serum cytokine production in the absence of B7-H1.

Conclusions/significance: Together, our data indicate that BM-DC express an endogenous CD1d ligand and B7-H1 to ihibit type II but not type I NKT cells. In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4(+) and NKT cell responses is enhanced.

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NKT cell hybridoma cells express PD-1 but only the type II NKT cells are stimulated by DC and are negatively regulated by B7-H1.A) NKT cell hybridoma cells s were stained for PD-1 and analyzed by FACS. The shaded histogram shows the isotype control staining and the black line shows PD-1 staining. B) DC from WT and B7-H1−/− mice were co-cultured with the indicated NKT hybridoma cells in the presence or absence of αGC (10 ng/ml). After 24 hours, the supernatants were tested for IL-2 content by ELISA. Results show 1 out of 4 representative and independent experiments. ** p<0.01.
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pone-0010800-g006: NKT cell hybridoma cells express PD-1 but only the type II NKT cells are stimulated by DC and are negatively regulated by B7-H1.A) NKT cell hybridoma cells s were stained for PD-1 and analyzed by FACS. The shaded histogram shows the isotype control staining and the black line shows PD-1 staining. B) DC from WT and B7-H1−/− mice were co-cultured with the indicated NKT hybridoma cells in the presence or absence of αGC (10 ng/ml). After 24 hours, the supernatants were tested for IL-2 content by ELISA. Results show 1 out of 4 representative and independent experiments. ** p<0.01.

Mentions: To further investigate if especially type II NKT cells were regulated by B7-H1 on DC we used different NKT cell lines, which were either related to type I (KT12 and BW58 r/m CD28) or type II NKT cells (XV19 and VIII24). All cell lines expressed PD-1, the ligand for B7-H1, at comparable levels (Figure 6A). We co-cultured DC from WT or B7-H1−/− mice with the different cell lines and found that only the type II NKT cells responded to the DC, which was indicated by the production of IL-2. Type I-related cell lines did only respond to DC in the presence of the CD1d-ligand αGC. The IL-2 response of the type II-related cells was even higher in the absence of B7-H1 on the DC showing that B7-H1 negatively regulates these cell lines (Figure 6B). It is of note that also the type I NKT cell lines showed an increased IL-2 production in the presence of αGC by using DC that were generated from B7-H1−/− mice (Figure 6B).


B7-H1-deficiency enhances the potential of tolerogenic dendritic cells by activating CD1d-restricted type II NKT cells.

Brandl C, Ortler S, Herrmann T, Cardell S, Lutz MB, Wiendl H - PLoS ONE (2010)

NKT cell hybridoma cells express PD-1 but only the type II NKT cells are stimulated by DC and are negatively regulated by B7-H1.A) NKT cell hybridoma cells s were stained for PD-1 and analyzed by FACS. The shaded histogram shows the isotype control staining and the black line shows PD-1 staining. B) DC from WT and B7-H1−/− mice were co-cultured with the indicated NKT hybridoma cells in the presence or absence of αGC (10 ng/ml). After 24 hours, the supernatants were tested for IL-2 content by ELISA. Results show 1 out of 4 representative and independent experiments. ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2875405&req=5

pone-0010800-g006: NKT cell hybridoma cells express PD-1 but only the type II NKT cells are stimulated by DC and are negatively regulated by B7-H1.A) NKT cell hybridoma cells s were stained for PD-1 and analyzed by FACS. The shaded histogram shows the isotype control staining and the black line shows PD-1 staining. B) DC from WT and B7-H1−/− mice were co-cultured with the indicated NKT hybridoma cells in the presence or absence of αGC (10 ng/ml). After 24 hours, the supernatants were tested for IL-2 content by ELISA. Results show 1 out of 4 representative and independent experiments. ** p<0.01.
Mentions: To further investigate if especially type II NKT cells were regulated by B7-H1 on DC we used different NKT cell lines, which were either related to type I (KT12 and BW58 r/m CD28) or type II NKT cells (XV19 and VIII24). All cell lines expressed PD-1, the ligand for B7-H1, at comparable levels (Figure 6A). We co-cultured DC from WT or B7-H1−/− mice with the different cell lines and found that only the type II NKT cells responded to the DC, which was indicated by the production of IL-2. Type I-related cell lines did only respond to DC in the presence of the CD1d-ligand αGC. The IL-2 response of the type II-related cells was even higher in the absence of B7-H1 on the DC showing that B7-H1 negatively regulates these cell lines (Figure 6B). It is of note that also the type I NKT cell lines showed an increased IL-2 production in the presence of αGC by using DC that were generated from B7-H1−/− mice (Figure 6B).

Bottom Line: Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC.Injections of B7-H1(-/-) TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-gamma production in the CNS.In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4(+) and NKT cell responses is enhanced.

View Article: PubMed Central - PubMed

Affiliation: Institute of Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.

ABSTRACT

Background: Dendritic cells (DC) can act tolerogenic at a semi-mature stage by induction of protective CD4(+) T cell and NKT cell responses.

Methodology/principal findings: Here we studied the role of the co-inhibitory molecule B7-H1 (PD-L1, CD274) on semi-mature DC that were generated from bone marrow (BM) cells of B7-H1(-/-) mice and applied to the model of Experimental Autoimmune Encephalomyelitis (EAE). Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC. Injections of B7-H1(-/-) TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-gamma production in the CNS. Experiments in CD1d(-/-) and Jalpha281(-/-) mice as well as with type I and II NKT cell lines indicated that only type II NKT cells but not type I NKT cells (invariant NKT cells) could be stimulated by an endogenous CD1d-ligand on DC and were responsible for the increased serum cytokine production in the absence of B7-H1.

Conclusions/significance: Together, our data indicate that BM-DC express an endogenous CD1d ligand and B7-H1 to ihibit type II but not type I NKT cells. In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4(+) and NKT cell responses is enhanced.

Show MeSH
Related in: MedlinePlus