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GITR Activation Positively Regulates Immune Responses against Toxoplasma gondii.

Costa FR, Mota CM, Santiago FM, Silva MV, Ferreira MD, Fonseca DM, Silva JS, Mineo JR, Mineo TW - PLoS ONE (2016)

Bottom Line: Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals.Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells.Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Imunoparasitologia "Dr. Mário Endsfeldz Camargo", Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Av. Amazonas s/n, Bloco 4C, Sala 4C01, 38405-320, Uberlândia, Minas Gerais, Brazil.

ABSTRACT
Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals. Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells. However, the precise role of this receptor in the context of T. gondii infection remains elusive. Therefore, the current study investigated the role of GITR activation in the immunoregulation mechanisms induced during the experimental infection of mice with T. gondii. Our data show that T. gondii infection slightly upregulates GITR expression in Treg cells and B cells, but the most robust increment in expression was observed in macrophages and dendritic cells. Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1. Several in vivo and in vitro analysis were performed to identify the cellular mechanisms involved in GITR activation upon infection, however no clear alterations were detected in the phenotype/function of macrophages, Tregs and B cells under treatment with DTA-1. Therefore, GITR appears as a potential target for intervention during infection by the parasite Toxoplasma gondii, even though further studies are still necessary to better characterize the immune response triggered by GITR activation during T. gondii infection.

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GITR activation does not alter antibody production.C57BL/6 mice were treated or not with 500 μg of DTA-1 one day before experimental infection. In the control group, PBS was administered. Infection was performed with 20 cysts injected i.p. A blood sample was collected on days 10, 20 and 30 after infection. Levels of IgG1 (A), IgG2a (B), Total IgG (C) and IgG2a/IgG1 ratio (D) were assessed by ELISA. Error bars indicate mean +/- SEM (n = 5/group).
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pone.0152622.g006: GITR activation does not alter antibody production.C57BL/6 mice were treated or not with 500 μg of DTA-1 one day before experimental infection. In the control group, PBS was administered. Infection was performed with 20 cysts injected i.p. A blood sample was collected on days 10, 20 and 30 after infection. Levels of IgG1 (A), IgG2a (B), Total IgG (C) and IgG2a/IgG1 ratio (D) were assessed by ELISA. Error bars indicate mean +/- SEM (n = 5/group).

Mentions: Although GITR expression was slightly modified in the presence of T. gondii tachyzoites, we also assessed whether DTA-1 treatment could affect specific antibody production in B cells and the number of Tregs during infection. In that sense, we measured the production kinetics of specific IgG antibodies, along with its subclasses IgG1 and IgG2a, in the serum of mice infected with T. gondii, treated or not with DTA-1. This assay showed that specific IgG production to parasite soluble antigens remained unchanged after treatment with DTA-1 (Fig 6), indicating that increased GITR signaling due to agonist antibody treatment did not alter antibody production and subclass profile in the course of T. gondii infection. In addition, previous reports using other experimental models have highlighted the role of GITR expression in Treg cells [20], so we evaluated whether GITR activation would affect the proportion of Tregs during infection in FoxP3GFP/+ mice. As shown in Fig 7, the activation of GITR with DTA-1 did not result in significant differences in T CD4+FoxP3+ cells after 5 days of T. gondii infection in vivo. Collectively, these results indicate that GITR activation is not involved in cytokine production by macrophages, antibody production by B cells or in proliferation by Treg cells.


GITR Activation Positively Regulates Immune Responses against Toxoplasma gondii.

Costa FR, Mota CM, Santiago FM, Silva MV, Ferreira MD, Fonseca DM, Silva JS, Mineo JR, Mineo TW - PLoS ONE (2016)

GITR activation does not alter antibody production.C57BL/6 mice were treated or not with 500 μg of DTA-1 one day before experimental infection. In the control group, PBS was administered. Infection was performed with 20 cysts injected i.p. A blood sample was collected on days 10, 20 and 30 after infection. Levels of IgG1 (A), IgG2a (B), Total IgG (C) and IgG2a/IgG1 ratio (D) were assessed by ELISA. Error bars indicate mean +/- SEM (n = 5/group).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4814089&req=5

pone.0152622.g006: GITR activation does not alter antibody production.C57BL/6 mice were treated or not with 500 μg of DTA-1 one day before experimental infection. In the control group, PBS was administered. Infection was performed with 20 cysts injected i.p. A blood sample was collected on days 10, 20 and 30 after infection. Levels of IgG1 (A), IgG2a (B), Total IgG (C) and IgG2a/IgG1 ratio (D) were assessed by ELISA. Error bars indicate mean +/- SEM (n = 5/group).
Mentions: Although GITR expression was slightly modified in the presence of T. gondii tachyzoites, we also assessed whether DTA-1 treatment could affect specific antibody production in B cells and the number of Tregs during infection. In that sense, we measured the production kinetics of specific IgG antibodies, along with its subclasses IgG1 and IgG2a, in the serum of mice infected with T. gondii, treated or not with DTA-1. This assay showed that specific IgG production to parasite soluble antigens remained unchanged after treatment with DTA-1 (Fig 6), indicating that increased GITR signaling due to agonist antibody treatment did not alter antibody production and subclass profile in the course of T. gondii infection. In addition, previous reports using other experimental models have highlighted the role of GITR expression in Treg cells [20], so we evaluated whether GITR activation would affect the proportion of Tregs during infection in FoxP3GFP/+ mice. As shown in Fig 7, the activation of GITR with DTA-1 did not result in significant differences in T CD4+FoxP3+ cells after 5 days of T. gondii infection in vivo. Collectively, these results indicate that GITR activation is not involved in cytokine production by macrophages, antibody production by B cells or in proliferation by Treg cells.

Bottom Line: Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals.Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells.Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Imunoparasitologia "Dr. Mário Endsfeldz Camargo", Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Av. Amazonas s/n, Bloco 4C, Sala 4C01, 38405-320, Uberlândia, Minas Gerais, Brazil.

ABSTRACT
Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals. Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells. However, the precise role of this receptor in the context of T. gondii infection remains elusive. Therefore, the current study investigated the role of GITR activation in the immunoregulation mechanisms induced during the experimental infection of mice with T. gondii. Our data show that T. gondii infection slightly upregulates GITR expression in Treg cells and B cells, but the most robust increment in expression was observed in macrophages and dendritic cells. Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1. Several in vivo and in vitro analysis were performed to identify the cellular mechanisms involved in GITR activation upon infection, however no clear alterations were detected in the phenotype/function of macrophages, Tregs and B cells under treatment with DTA-1. Therefore, GITR appears as a potential target for intervention during infection by the parasite Toxoplasma gondii, even though further studies are still necessary to better characterize the immune response triggered by GITR activation during T. gondii infection.

Show MeSH
Related in: MedlinePlus