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Liver accumulation of Plasmodium chabaudi-infected red blood cells and modulation of regulatory T cell and dendritic cell responses.

Medeiros MM, da Silva HB, Reis AS, Barboza R, Thompson J, Lima MR, Marinho CR, Tadokoro CE - PLoS ONE (2013)

Bottom Line: On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo.It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression.Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.

View Article: PubMed Central - PubMed

Affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.

ABSTRACT
It is postulated that accumulation of malaria-infected Red Blood Cells (iRBCs) in the liver could be a parasitic escape mechanism against full destruction by the host immune system. Therefore, we evaluated the in vivo mechanism of this accumulation and its potential immunological consequences. A massive liver accumulation of P. c. chabaudi AS-iRBCs (Pc-iRBCs) was observed by intravital microscopy along with an over expression of ICAM-1 on day 7 of the infection, as measured by qRT-PCR. Phenotypic changes were also observed in regulatory T cells (Tregs) and dendritic cells (DCs) that were isolated from infected livers, which indicate a functional role for Tregs in the regulation of the liver inflammatory immune response. In fact, the suppressive function of liver-Tregs was in vitro tested, which demonstrated the capacity of these cells to suppress naive T cell activation to the same extent as that observed for spleen-Tregs. On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo. In our experiments, we observed a similar lack of in vitro proliferative capacity in liver CD4+ T cells that were isolated on day 7 of infection. It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression. Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.

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Infection with iRBCs induces alterations on Tregs and APCs inside the liver.Foxp3-GFP or CD11c-YFP mice were intraperitoneally infected or not with Pc-iRBCs. All animals were divided into three groups: Control (non-infected; open columns); infected, on day 7 of infection (INF d7; grey columns); or infected, on day 21 of infection (INF d21; black columns). Liver cells were stained with MAbs against a panel of surface molecules to identify different types and subtypes of leukocytes, as well as the expression levels of some proteins. (A) Numbers and percentages of Foxp3+CD4+ cell (Tregs) in the liver samples. (B) CD28 and GITR expression levels on Tregs. (C) Percentages of lymphoid (LDCs) or myeloid (mDCs) DCs in the liver samples. (D) MHCII, CD86, and F4/80 expression levels on DC subtypes and macrophages. These results are representative of 3 repetitions.
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pone-0081409-g004: Infection with iRBCs induces alterations on Tregs and APCs inside the liver.Foxp3-GFP or CD11c-YFP mice were intraperitoneally infected or not with Pc-iRBCs. All animals were divided into three groups: Control (non-infected; open columns); infected, on day 7 of infection (INF d7; grey columns); or infected, on day 21 of infection (INF d21; black columns). Liver cells were stained with MAbs against a panel of surface molecules to identify different types and subtypes of leukocytes, as well as the expression levels of some proteins. (A) Numbers and percentages of Foxp3+CD4+ cell (Tregs) in the liver samples. (B) CD28 and GITR expression levels on Tregs. (C) Percentages of lymphoid (LDCs) or myeloid (mDCs) DCs in the liver samples. (D) MHCII, CD86, and F4/80 expression levels on DC subtypes and macrophages. These results are representative of 3 repetitions.

Mentions: Treg numbers were increased in INF d7 group in comparison to Control or INF d21 groups (Figure 4A), and these cells expressed higher levels of CD28 and GITR than the other two groups (Figure 4B). No differences were observed in CTLA-4 or CD25 expression levels on INF d7 and INF d21 groups in comparison to Control group (Figure S4, B and C). Moreover, cells from INF d21 group had similar CD28 or GITR expression levels as cells from Control group (Figure S4C). Despite the finding that CD8+ Treg numbers in INF d7 group were higher than those in Control or INF d21 groups, these numbers were still quite lower than CD4 Treg numbers (Figure S4Avs. Figure 4A); double-positive (DP) CD4+CD8+ Treg numbers were similarly very low across all groups (Figure S4A).


Liver accumulation of Plasmodium chabaudi-infected red blood cells and modulation of regulatory T cell and dendritic cell responses.

Medeiros MM, da Silva HB, Reis AS, Barboza R, Thompson J, Lima MR, Marinho CR, Tadokoro CE - PLoS ONE (2013)

Infection with iRBCs induces alterations on Tregs and APCs inside the liver.Foxp3-GFP or CD11c-YFP mice were intraperitoneally infected or not with Pc-iRBCs. All animals were divided into three groups: Control (non-infected; open columns); infected, on day 7 of infection (INF d7; grey columns); or infected, on day 21 of infection (INF d21; black columns). Liver cells were stained with MAbs against a panel of surface molecules to identify different types and subtypes of leukocytes, as well as the expression levels of some proteins. (A) Numbers and percentages of Foxp3+CD4+ cell (Tregs) in the liver samples. (B) CD28 and GITR expression levels on Tregs. (C) Percentages of lymphoid (LDCs) or myeloid (mDCs) DCs in the liver samples. (D) MHCII, CD86, and F4/80 expression levels on DC subtypes and macrophages. These results are representative of 3 repetitions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842419&req=5

pone-0081409-g004: Infection with iRBCs induces alterations on Tregs and APCs inside the liver.Foxp3-GFP or CD11c-YFP mice were intraperitoneally infected or not with Pc-iRBCs. All animals were divided into three groups: Control (non-infected; open columns); infected, on day 7 of infection (INF d7; grey columns); or infected, on day 21 of infection (INF d21; black columns). Liver cells were stained with MAbs against a panel of surface molecules to identify different types and subtypes of leukocytes, as well as the expression levels of some proteins. (A) Numbers and percentages of Foxp3+CD4+ cell (Tregs) in the liver samples. (B) CD28 and GITR expression levels on Tregs. (C) Percentages of lymphoid (LDCs) or myeloid (mDCs) DCs in the liver samples. (D) MHCII, CD86, and F4/80 expression levels on DC subtypes and macrophages. These results are representative of 3 repetitions.
Mentions: Treg numbers were increased in INF d7 group in comparison to Control or INF d21 groups (Figure 4A), and these cells expressed higher levels of CD28 and GITR than the other two groups (Figure 4B). No differences were observed in CTLA-4 or CD25 expression levels on INF d7 and INF d21 groups in comparison to Control group (Figure S4, B and C). Moreover, cells from INF d21 group had similar CD28 or GITR expression levels as cells from Control group (Figure S4C). Despite the finding that CD8+ Treg numbers in INF d7 group were higher than those in Control or INF d21 groups, these numbers were still quite lower than CD4 Treg numbers (Figure S4Avs. Figure 4A); double-positive (DP) CD4+CD8+ Treg numbers were similarly very low across all groups (Figure S4A).

Bottom Line: On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo.It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression.Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.

View Article: PubMed Central - PubMed

Affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.

ABSTRACT
It is postulated that accumulation of malaria-infected Red Blood Cells (iRBCs) in the liver could be a parasitic escape mechanism against full destruction by the host immune system. Therefore, we evaluated the in vivo mechanism of this accumulation and its potential immunological consequences. A massive liver accumulation of P. c. chabaudi AS-iRBCs (Pc-iRBCs) was observed by intravital microscopy along with an over expression of ICAM-1 on day 7 of the infection, as measured by qRT-PCR. Phenotypic changes were also observed in regulatory T cells (Tregs) and dendritic cells (DCs) that were isolated from infected livers, which indicate a functional role for Tregs in the regulation of the liver inflammatory immune response. In fact, the suppressive function of liver-Tregs was in vitro tested, which demonstrated the capacity of these cells to suppress naive T cell activation to the same extent as that observed for spleen-Tregs. On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo. In our experiments, we observed a similar lack of in vitro proliferative capacity in liver CD4+ T cells that were isolated on day 7 of infection. It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression. Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.

Show MeSH
Related in: MedlinePlus