Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection.
<h4>Background</h4>The Trypanosoma cruzi infection is associated with severe T cell unresponsiveness to antigens and mitogens characterized by decreased IL-2 synthesis. Trypanosoma cruzi mucin (Tc Muc) has been implicated in this phenomenom. These molecules contain a unique type of glyco...
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2013
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oai:doaj.org-article:320743c7212b4dbe908b593066abe8412021-11-18T08:49:16ZInhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection.1932-620310.1371/journal.pone.0077568https://doaj.org/article/320743c7212b4dbe908b593066abe8412013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24204874/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The Trypanosoma cruzi infection is associated with severe T cell unresponsiveness to antigens and mitogens characterized by decreased IL-2 synthesis. Trypanosoma cruzi mucin (Tc Muc) has been implicated in this phenomenom. These molecules contain a unique type of glycosylation consisting of several sialylated O-glycans linked to the protein backbone via N-acetylglucosamine residues.<h4>Methodology/principal findings</h4>In this study, we evaluated the ability of Tc Muc to modulate the activation of CD4(+) T cells. Our data show that cross-linking of CD3 on naïve CD4(+) T cells in the presence of Tc Muc resulted in the inhibition of both cytokine secretion and proliferation. We further show that the sialylated O-Linked Glycan residues from tc mucin potentiate the suppression of T cell response by inducing G1-phase cell cycle arrest associated with upregulation of mitogen inhibitor p27(kip1). These inhibitory effects cannot be reversed by the addition of exogenous IL-2, rendering CD4(+) T cells anergic when activated by TCR triggering. Additionally, in vivo administration of Tc Muc during T. cruzi infection enhanced parasitemia and aggravated heart damage. Analysis of recall responses during infection showed lower frequencies of IFN-γ producing CD4(+) T cells in the spleen of Tc Muc treated mice, compared to untreated controls.<h4>Conclusions/significance</h4>Our results indicate that Tc Muc mediates inhibitory efects on CD4(+) T expansion and cytokine production, by blocking cell cycle progression in the G1 phase. We propose that the sialyl motif of Tc Muc is able to interact with sialic acid-binding Ig-like lectins (Siglecs) on CD4(+) T cells, which may allow the parasite to modulate the immune system.Marise Pinheiro NunesBárbara FortesJoão Luiz Silva-FilhoEugênia Terra-GranadoLeonardo SantosLuciana CondeIsadora de Araújo OliveiraLeonardo Freire-de-LimaMarina Vieira MartinsAna Acacia Sá PinheiroChristina Maeda TakyiaCélio Geraldo Freire-de-LimaAdriane Regina TodeschiniGeorge Alexandre DosreisAlexandre MorrotPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e77568 (2013) |
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| spellingShingle |
Medicine R Science Q Marise Pinheiro Nunes Bárbara Fortes João Luiz Silva-Filho Eugênia Terra-Granado Leonardo Santos Luciana Conde Isadora de Araújo Oliveira Leonardo Freire-de-Lima Marina Vieira Martins Ana Acacia Sá Pinheiro Christina Maeda Takyia Célio Geraldo Freire-de-Lima Adriane Regina Todeschini George Alexandre Dosreis Alexandre Morrot Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. |
| description |
<h4>Background</h4>The Trypanosoma cruzi infection is associated with severe T cell unresponsiveness to antigens and mitogens characterized by decreased IL-2 synthesis. Trypanosoma cruzi mucin (Tc Muc) has been implicated in this phenomenom. These molecules contain a unique type of glycosylation consisting of several sialylated O-glycans linked to the protein backbone via N-acetylglucosamine residues.<h4>Methodology/principal findings</h4>In this study, we evaluated the ability of Tc Muc to modulate the activation of CD4(+) T cells. Our data show that cross-linking of CD3 on naïve CD4(+) T cells in the presence of Tc Muc resulted in the inhibition of both cytokine secretion and proliferation. We further show that the sialylated O-Linked Glycan residues from tc mucin potentiate the suppression of T cell response by inducing G1-phase cell cycle arrest associated with upregulation of mitogen inhibitor p27(kip1). These inhibitory effects cannot be reversed by the addition of exogenous IL-2, rendering CD4(+) T cells anergic when activated by TCR triggering. Additionally, in vivo administration of Tc Muc during T. cruzi infection enhanced parasitemia and aggravated heart damage. Analysis of recall responses during infection showed lower frequencies of IFN-γ producing CD4(+) T cells in the spleen of Tc Muc treated mice, compared to untreated controls.<h4>Conclusions/significance</h4>Our results indicate that Tc Muc mediates inhibitory efects on CD4(+) T expansion and cytokine production, by blocking cell cycle progression in the G1 phase. We propose that the sialyl motif of Tc Muc is able to interact with sialic acid-binding Ig-like lectins (Siglecs) on CD4(+) T cells, which may allow the parasite to modulate the immune system. |
| format |
article |
| author |
Marise Pinheiro Nunes Bárbara Fortes João Luiz Silva-Filho Eugênia Terra-Granado Leonardo Santos Luciana Conde Isadora de Araújo Oliveira Leonardo Freire-de-Lima Marina Vieira Martins Ana Acacia Sá Pinheiro Christina Maeda Takyia Célio Geraldo Freire-de-Lima Adriane Regina Todeschini George Alexandre Dosreis Alexandre Morrot |
| author_facet |
Marise Pinheiro Nunes Bárbara Fortes João Luiz Silva-Filho Eugênia Terra-Granado Leonardo Santos Luciana Conde Isadora de Araújo Oliveira Leonardo Freire-de-Lima Marina Vieira Martins Ana Acacia Sá Pinheiro Christina Maeda Takyia Célio Geraldo Freire-de-Lima Adriane Regina Todeschini George Alexandre Dosreis Alexandre Morrot |
| author_sort |
Marise Pinheiro Nunes |
| title |
Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. |
| title_short |
Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. |
| title_full |
Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. |
| title_fullStr |
Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. |
| title_full_unstemmed |
Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. |
| title_sort |
inhibitory effects of trypanosoma cruzi sialoglycoproteins on cd4+ t cells are associated with increased susceptibility to infection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/320743c7212b4dbe908b593066abe841 |
| work_keys_str_mv |
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