title: Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Marise Pinheiro
authors.initials: MP
authors.lastname: Nunes
authors.forename: Bárbara
authors.initials: B
authors.lastname: Fortes
authors.forename: João Luiz
authors.initials: JL
authors.lastname: Silva-Filho
authors.forename: Eugênia
authors.initials: E
authors.lastname: Terra-Granado
authors.forename: Leonardo
authors.initials: L
authors.lastname: Santos
authors.forename: Luciana
authors.initials: L
authors.lastname: Conde
authors.forename: Isadora
authors.initials: I
authors.lastname: de Araújo Oliveira
authors.forename: Leonardo
authors.initials: L
authors.lastname: Freire-de-Lima
authors.forename: Marina Vieira
authors.initials: MV
authors.lastname: Martins
authors.forename: Ana Acacia Sá
authors.initials: AA
authors.lastname: Pinheiro
authors.forename: Christina Maeda
authors.initials: CM
authors.lastname: Takyia
authors.forename: Célio Geraldo
authors.initials: CG
authors.lastname: Freire-de-Lima
authors.forename: Adriane Regina
authors.initials: AR
authors.lastname: Todeschini
authors.forename: George Alexandre
authors.initials: GA
authors.lastname: Dosreis
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morrot
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D059447:Cell Cycle Checkpoints / Q000276:immunology; D049109:Cell Proliferation; D014355:Chagas Disease / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology*; D016193:G1 Phase / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000276:immunology; D012795:Sialoglycoproteins / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D007376:Interleukin-2; D009077:Mucins; D012795:Sialoglycoproteins; D007371:Interferon-gamma