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Immune evasion by Yersinia enterocolitica: differential targeting of dendritic cell subpopulations in vivo.

Autenrieth SE, Linzer TR, Hiller C, Keller B, Warnke P, Köberle M, Bohn E, Biedermann T, Bühring HJ, Hämmerling GJ, Rammensee HG, Autenrieth IB - PLoS Pathog. (2010)

Bottom Line: The decreased number of DC subsets, which was dependent on TLR4 and TRIF signaling, was the result of a faster proliferation and suppressed de novo DC generation.The data suggest that these effects might be caused directly by injection of Yops into DCs and indirectly by affecting the homeostasis of CD4(+) and CD8α(+) DCs.These events may contribute to reduced T-cell proliferation and immune evasion of Ye.

View Article: PubMed Central - PubMed

Affiliation: Interfakultäres Institut für Zellbiologie, Universität Tübingen, Tübingen, Germany. Stella.Autenrieth@medizin.uni-tuebingen.de

ABSTRACT
CD4(+) T cells are essential for the control of Yersinia enterocolitica (Ye) infection in mice. Ye can inhibit dendritic cell (DC) antigen uptake and degradation, maturation and subsequently T-cell activation in vitro. Here we investigated the effects of Ye infection on splenic DCs and T-cell proliferation in an experimental mouse infection model. We found that OVA-specific CD4(+) T cells had a reduced potential to proliferate when stimulated with OVA after infection with Ye compared to control mice. Additionally, proliferation of OVA-specific CD4(+) T cells was markedly reduced when cultured with splenic CD8α(+) DCs from Ye infected mice in the presence of OVA. In contrast, T-cell proliferation was not impaired in cultures with CD4(+) or CD4(-)CD8α(-) DCs isolated from Ye infected mice. However, OVA uptake and degradation as well as cytokine production were impaired in CD8α(+) DCs, but not in CD4(+) and CD4(-)CD8α(-) DCs after Ye infection. Pathogenicity factors (Yops) from Ye were most frequently injected into CD8α(+) DCs, resulting in less MHC class II and CD86 expression than on non-injected CD8α(+) DCs. Three days post infection with Ye the number of splenic CD8α(+) and CD4(+) DCs was reduced by 50% and 90%, respectively. The decreased number of DC subsets, which was dependent on TLR4 and TRIF signaling, was the result of a faster proliferation and suppressed de novo DC generation. Together, we show that Ye infection negatively regulates the stimulatory capacity of some but not all splenic DC subpopulations in vivo. This leads to differential antigen uptake and degradation, cytokine production, cell loss, and cell death rates in various DC subpopulations. The data suggest that these effects might be caused directly by injection of Yops into DCs and indirectly by affecting the homeostasis of CD4(+) and CD8α(+) DCs. These events may contribute to reduced T-cell proliferation and immune evasion of Ye.

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Immunofluorescence analysis of DCs from mice infected with Ye.C57BL/6 mice were injected i.v. with 5×104 Ye pYV+ or PBS. (A) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red), Bar  = 100 µm. (B) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red, surface staining) and TUNEL (green, nuclear staining). Arrowheads indicate double positive cells, A abscesses, LF lymphoid follicle.
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ppat-1001212-g006: Immunofluorescence analysis of DCs from mice infected with Ye.C57BL/6 mice were injected i.v. with 5×104 Ye pYV+ or PBS. (A) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red), Bar  = 100 µm. (B) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red, surface staining) and TUNEL (green, nuclear staining). Arrowheads indicate double positive cells, A abscesses, LF lymphoid follicle.

Mentions: Mice treated with LPS or infected with E. coli showed a transient loss of CD4+ and CD8α+ DCs in the spleen by apoptosis [51]. Here, apoptosis was mediated via TLR4 and TRIF signaling. To elucidate whether Ye induces DC death in vivo, the number of live and dead splenic DC subpopulations from Ye-infected and PBS-treated mice were analyzed (Fig. 5). Upon infection with Ye CD4+ (90%) and to a lesser extent CD8α+ DCs (65%) were lost (Fig. 5A and B). Specifically, the number of CD4+ and CD8α+ DCs declined from 1.1×106 cells and 4.7×105/spleen in PBS-treated mice to 1×105 cells and 1.7×105/spleen three days p.i. with Ye, respectively (Fig. 5B). In contrast, the number of CD4−CD8α− DCs in the spleen increased upon Ye infection compared to that in control mice. In addition, we did immunofluorescence microscopy of cryosections from the spleen of Ye or PBS-treated mice analyzing the CD11c+ cells. Ye infection leads to the migration of CD11c+ cells from the marginal zone (PBS-treated mice) to the T-cell zone of the lymphoid follicles and to a reduced number of CD11c+ cells three days p.i. (Fig. 6A). CD4 or CD8α down-regulation on CD4+ or CD8α+ DCs was not observed upon infection of splenocytes with Ye in vitro (Fig. S2), indicating that the loss of DC subpopulations is not due to simple down-regulation of these receptors.


Immune evasion by Yersinia enterocolitica: differential targeting of dendritic cell subpopulations in vivo.

Autenrieth SE, Linzer TR, Hiller C, Keller B, Warnke P, Köberle M, Bohn E, Biedermann T, Bühring HJ, Hämmerling GJ, Rammensee HG, Autenrieth IB - PLoS Pathog. (2010)

Immunofluorescence analysis of DCs from mice infected with Ye.C57BL/6 mice were injected i.v. with 5×104 Ye pYV+ or PBS. (A) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red), Bar  = 100 µm. (B) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red, surface staining) and TUNEL (green, nuclear staining). Arrowheads indicate double positive cells, A abscesses, LF lymphoid follicle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991265&req=5

ppat-1001212-g006: Immunofluorescence analysis of DCs from mice infected with Ye.C57BL/6 mice were injected i.v. with 5×104 Ye pYV+ or PBS. (A) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red), Bar  = 100 µm. (B) Cryosections of spleen from mice treated with PBS or Ye were stained for CD11c (red, surface staining) and TUNEL (green, nuclear staining). Arrowheads indicate double positive cells, A abscesses, LF lymphoid follicle.
Mentions: Mice treated with LPS or infected with E. coli showed a transient loss of CD4+ and CD8α+ DCs in the spleen by apoptosis [51]. Here, apoptosis was mediated via TLR4 and TRIF signaling. To elucidate whether Ye induces DC death in vivo, the number of live and dead splenic DC subpopulations from Ye-infected and PBS-treated mice were analyzed (Fig. 5). Upon infection with Ye CD4+ (90%) and to a lesser extent CD8α+ DCs (65%) were lost (Fig. 5A and B). Specifically, the number of CD4+ and CD8α+ DCs declined from 1.1×106 cells and 4.7×105/spleen in PBS-treated mice to 1×105 cells and 1.7×105/spleen three days p.i. with Ye, respectively (Fig. 5B). In contrast, the number of CD4−CD8α− DCs in the spleen increased upon Ye infection compared to that in control mice. In addition, we did immunofluorescence microscopy of cryosections from the spleen of Ye or PBS-treated mice analyzing the CD11c+ cells. Ye infection leads to the migration of CD11c+ cells from the marginal zone (PBS-treated mice) to the T-cell zone of the lymphoid follicles and to a reduced number of CD11c+ cells three days p.i. (Fig. 6A). CD4 or CD8α down-regulation on CD4+ or CD8α+ DCs was not observed upon infection of splenocytes with Ye in vitro (Fig. S2), indicating that the loss of DC subpopulations is not due to simple down-regulation of these receptors.

Bottom Line: The decreased number of DC subsets, which was dependent on TLR4 and TRIF signaling, was the result of a faster proliferation and suppressed de novo DC generation.The data suggest that these effects might be caused directly by injection of Yops into DCs and indirectly by affecting the homeostasis of CD4(+) and CD8α(+) DCs.These events may contribute to reduced T-cell proliferation and immune evasion of Ye.

View Article: PubMed Central - PubMed

Affiliation: Interfakultäres Institut für Zellbiologie, Universität Tübingen, Tübingen, Germany. Stella.Autenrieth@medizin.uni-tuebingen.de

ABSTRACT
CD4(+) T cells are essential for the control of Yersinia enterocolitica (Ye) infection in mice. Ye can inhibit dendritic cell (DC) antigen uptake and degradation, maturation and subsequently T-cell activation in vitro. Here we investigated the effects of Ye infection on splenic DCs and T-cell proliferation in an experimental mouse infection model. We found that OVA-specific CD4(+) T cells had a reduced potential to proliferate when stimulated with OVA after infection with Ye compared to control mice. Additionally, proliferation of OVA-specific CD4(+) T cells was markedly reduced when cultured with splenic CD8α(+) DCs from Ye infected mice in the presence of OVA. In contrast, T-cell proliferation was not impaired in cultures with CD4(+) or CD4(-)CD8α(-) DCs isolated from Ye infected mice. However, OVA uptake and degradation as well as cytokine production were impaired in CD8α(+) DCs, but not in CD4(+) and CD4(-)CD8α(-) DCs after Ye infection. Pathogenicity factors (Yops) from Ye were most frequently injected into CD8α(+) DCs, resulting in less MHC class II and CD86 expression than on non-injected CD8α(+) DCs. Three days post infection with Ye the number of splenic CD8α(+) and CD4(+) DCs was reduced by 50% and 90%, respectively. The decreased number of DC subsets, which was dependent on TLR4 and TRIF signaling, was the result of a faster proliferation and suppressed de novo DC generation. Together, we show that Ye infection negatively regulates the stimulatory capacity of some but not all splenic DC subpopulations in vivo. This leads to differential antigen uptake and degradation, cytokine production, cell loss, and cell death rates in various DC subpopulations. The data suggest that these effects might be caused directly by injection of Yops into DCs and indirectly by affecting the homeostasis of CD4(+) and CD8α(+) DCs. These events may contribute to reduced T-cell proliferation and immune evasion of Ye.

Show MeSH
Related in: MedlinePlus