Inhibitory Effects of Trypanosoma cruzi Sialoglycoproteins on CD4+ T Cells Are Associated with Increased Susceptibility to Infection

Abstract

BackgroundThe 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.Methodology/Principal FindingsIn 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 p27kip1. 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/SignificanceOur 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.

CD4+T Cells Promote Antibody Production but Not Sustained Affinity Maturation during Borrelia burgdorferi Infection

“…CD4 T cells and T-dependent antibody responses are targets for attack or evasion by many highly successful viral (51,52), bacterial (53,54), and parasitic pathogens (55,56). Thus, reducing the effectiveness of CD4 T cells during B. burgdorferi infection to support long-term humoral immunity and perhaps other mechanisms of immune protection would not be without precedent.…”

Role of Inactive and Active Trypanosoma cruzi Trans-sialidases on T Cell Homing and Secretion of Inflammatory Cytokines

“…T cells were cultured in DMEM supplemented with 2 mM glutamine, 5 × 10 -5 M 2-Mercaptoethanol (2-ME), 10 μg/mL gentamicin, 1 mM sodium pyruvate, and 0.1 mM MEM non-essential amino acids (all from Gibco TM , Invitrogen Corporation) plus 1% Nutridoma-SP (Roche, Germany) instead of FBS (Nunes et al, 2013). …”

Immune Evasion Strategies ofTrypanosoma cruzi

“…They also impair host dendritic cell function as demonstrated by inhibition of the production of IL-12 [ 56 ]. This inhibition may occur at the transcriptional level, since the T. cruzi -derived mucins are able to inhibit transcription of the IL-2 gene in T cells [ 33 , 34 ], which also occurs when T cell activation and proliferation are blocked in response to mitogens and antigens [ 57 ]. The parasite sialoglycoproteins also inhibit early events in T cell activation, in particular tyrosine phosphorylation of the adapter protein SLP-76 and the tyrosine kinase ZAP-70 [ 37 ].…”