Trypanosoma cruzi trans-sialidase prevents Th1 elicitation via interleukin 10 and downregulates Th1 effector cells

RUIZ DÍAZ P*; MUCCI J*#; MEIRA MA; BOGLIOTTI Y; MUSIKANT D; LEGUIZAMÓN MS; CAMPETELLA O#

INFECTION AND IMMUNITY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2015 vol. 83 p. 2099 - 2108

0019-9567

Pablo Ruiz Díaz y Juan Mucci co-primeros autores. Juan Mucci y Oscar Campetella corresponding authors. The trans-sialidases (TSs) from Trypanosoma cruzi, the agent of Chagas disease, are virulence factors shed to the bloodstream that induces strong alterations in the immune system. Here we report that enzymatically active TS (aTS) or its lectin-like isoform (iTS) disturb CD4 T cell physiology inducing downregulation of Th1 cell functionality and in vivo cell-expansion. By using ovalbumin-specific DO11.10 cells as tracers of Th1-phenotype developing clones, we found that the infection induced significant amounts of IFN-γ but low IL-2 and increased IL-4 production in vivo, in agreement with a mixed T helper response. Production of cytokines associated with Th2-phenotype was prevented by passive transference of TS-neutralizing antibodies. TSs also reduced the T cell receptor signaling, assayed by Zap-70 phosphorylation. TSs also reduced IL-2 and IFN-γ secretion with a concomitant increased IL-4 production, then unbalancing the CD4 T cell response towards the Th2 phenotype. This effect was prevented with IL-10-neutralizing antibodies or by using IL10-/- antigen-presenting cells, supporting the subversion of this regulatory pathway. In support, TSs stimulated IL-10 secretion by antigen-presenting cells during their interaction with CD4 T cells. When polarized cells were stimulated in the presence of TSs, secretion of IL-2 and IFN-γ was strongly downregulated in Th1 while IL-2 production was upregulated in Th2 cells. Although Th1 response is associated with host survival, it may simultaneously induce extensive damage to infected tissues. Thus, by delaying the elicitation of Th1-response and limit its effector properties, TSs restrain cell response supporting T. cruzi colonization and persistence while favoring host survival.