Limits...
Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

Liu YJ, Li K, Yang L, Tang ST, Wang XX, Cao GQ, Li S, Lei HY, Zhang X - PLoS ONE (2015)

Bottom Line: By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved.The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated.In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT
Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

No MeSH data available.


Related in: MedlinePlus

Suppression capability of “ill” Tregs on the proliferation of Th17 originating from CD4+ naïve T cells ex vivo.(A) Tregs isolated from BA mice were injected i.p. 3 days post infection. The survival rate of mice that received Tregs from BA mice was significantly lower than mice that received Tregs from normal mice (P = 0.0107). (B) CD4+ naïve T cells were isolated from splenic MNCs of 8-week-old adult Balb/c mice. Tregs were obtained from splenic MNC of either RRV or saline primed 7 days old mice. Different ratio of CD4+ naïve T cell and Tregs were cultured in the conditions described above (TGF-β, IL-6, IL-1α, anti-IL-4, anti-IL-12, anti-IFN-γ, and stimulated with plate-bound anti-CD3and soluble anti-CD28 MAbs for 7 days). IL-17A in the supernatant was measured by ELISA. The percentage of relative suppression was calculated by the formula: 1-(IL-17A in the presence of Treg)/(IL-17A in the absence of Treg). 10–12 pooled spleens were used in experiments. * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556529&req=5

pone.0136214.g005: Suppression capability of “ill” Tregs on the proliferation of Th17 originating from CD4+ naïve T cells ex vivo.(A) Tregs isolated from BA mice were injected i.p. 3 days post infection. The survival rate of mice that received Tregs from BA mice was significantly lower than mice that received Tregs from normal mice (P = 0.0107). (B) CD4+ naïve T cells were isolated from splenic MNCs of 8-week-old adult Balb/c mice. Tregs were obtained from splenic MNC of either RRV or saline primed 7 days old mice. Different ratio of CD4+ naïve T cell and Tregs were cultured in the conditions described above (TGF-β, IL-6, IL-1α, anti-IL-4, anti-IL-12, anti-IFN-γ, and stimulated with plate-bound anti-CD3and soluble anti-CD28 MAbs for 7 days). IL-17A in the supernatant was measured by ELISA. The percentage of relative suppression was calculated by the formula: 1-(IL-17A in the presence of Treg)/(IL-17A in the absence of Treg). 10–12 pooled spleens were used in experiments. * P<0.05.

Mentions: Despite the fact that the absolute number of Treg cells was increased, the proliferation of Th17 cells and the inflammation of bile ducts were not suppressed in BA mice. Therefore, we suspected that the ability of Treg cells to suppress Th17 cells was impaired in BA. To determine directly the suppressive effect of the Treg cells on Th17 cells, Treg cells isolated from 7-day-old BA mice were injected i.p. into RRV-primed mice at 3 days post-infection. These Treg cells were isolated from the spleen (which is a natural reservoir for Treg cells) with similar Treg cell responses that were observed in the liver following RRV infection. The survival rate of this group of mice was 52.4%, which was significantly decreased compared with the survival rate of mice after AT of normal Treg cells (84.6%, P = 0.011, Fig 5A).


Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

Liu YJ, Li K, Yang L, Tang ST, Wang XX, Cao GQ, Li S, Lei HY, Zhang X - PLoS ONE (2015)

Suppression capability of “ill” Tregs on the proliferation of Th17 originating from CD4+ naïve T cells ex vivo.(A) Tregs isolated from BA mice were injected i.p. 3 days post infection. The survival rate of mice that received Tregs from BA mice was significantly lower than mice that received Tregs from normal mice (P = 0.0107). (B) CD4+ naïve T cells were isolated from splenic MNCs of 8-week-old adult Balb/c mice. Tregs were obtained from splenic MNC of either RRV or saline primed 7 days old mice. Different ratio of CD4+ naïve T cell and Tregs were cultured in the conditions described above (TGF-β, IL-6, IL-1α, anti-IL-4, anti-IL-12, anti-IFN-γ, and stimulated with plate-bound anti-CD3and soluble anti-CD28 MAbs for 7 days). IL-17A in the supernatant was measured by ELISA. The percentage of relative suppression was calculated by the formula: 1-(IL-17A in the presence of Treg)/(IL-17A in the absence of Treg). 10–12 pooled spleens were used in experiments. * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556529&req=5

pone.0136214.g005: Suppression capability of “ill” Tregs on the proliferation of Th17 originating from CD4+ naïve T cells ex vivo.(A) Tregs isolated from BA mice were injected i.p. 3 days post infection. The survival rate of mice that received Tregs from BA mice was significantly lower than mice that received Tregs from normal mice (P = 0.0107). (B) CD4+ naïve T cells were isolated from splenic MNCs of 8-week-old adult Balb/c mice. Tregs were obtained from splenic MNC of either RRV or saline primed 7 days old mice. Different ratio of CD4+ naïve T cell and Tregs were cultured in the conditions described above (TGF-β, IL-6, IL-1α, anti-IL-4, anti-IL-12, anti-IFN-γ, and stimulated with plate-bound anti-CD3and soluble anti-CD28 MAbs for 7 days). IL-17A in the supernatant was measured by ELISA. The percentage of relative suppression was calculated by the formula: 1-(IL-17A in the presence of Treg)/(IL-17A in the absence of Treg). 10–12 pooled spleens were used in experiments. * P<0.05.
Mentions: Despite the fact that the absolute number of Treg cells was increased, the proliferation of Th17 cells and the inflammation of bile ducts were not suppressed in BA mice. Therefore, we suspected that the ability of Treg cells to suppress Th17 cells was impaired in BA. To determine directly the suppressive effect of the Treg cells on Th17 cells, Treg cells isolated from 7-day-old BA mice were injected i.p. into RRV-primed mice at 3 days post-infection. These Treg cells were isolated from the spleen (which is a natural reservoir for Treg cells) with similar Treg cell responses that were observed in the liver following RRV infection. The survival rate of this group of mice was 52.4%, which was significantly decreased compared with the survival rate of mice after AT of normal Treg cells (84.6%, P = 0.011, Fig 5A).

Bottom Line: By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved.The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated.In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT
Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

No MeSH data available.


Related in: MedlinePlus