immunology of infectious and parasitic diseases - XXXVII Congress ...

INDUCTION OF TH17 LYMPHOCYTES CONTROLS MYOCARDITIS DURING
Trypanosoma cruzi INFECTION BY RESTRAINING A DETRIMENTAL TH1
RESPONSE
TIAGO DA SILVA MEDINA (1) ; GRACE KELLY SILVA (1) ; DENISE MORAIS
FONSECA (1) ; RENATA SESTI-COSTA (1) ; MARIA CLÁUDIA SILVA (1) ;
BERNARD RYFFEL (2) ; JOÃO SANTANA SILVA (1) .
(1) Laboratório de Imunoparasitologia da Faculdade de Medicina de
Ribeirão Preto, Universidade de São Paulo - Ribeirão Preto, Brasil
(FMRP-USP).
(2) Centre National de la Recherche Scientifique (CNRS), Orléans, France.
Introduction: Trypanosoma cruzi infection predominantly induces a Th1
response to control the parasite proliferation; nevertheless an exacerbated Th1
response is deleterious to the host. Objective: Because the microenvironment
plays a crucial role during CD4 + T cell differentiation, we sought to understand
how the immune response is regulated in the absence of molecules involved
with Th17 lymphocytes differentiation and maintenance. Results: After infecting
WT, IL-17R -/- , IL-23 -/- and IL-6 -/- mice with 10 3 forms of T. cruzi (Y strain), we
observed that IL-17R -/- , IL-23 -/- and IL-6 -/- mice rapidly succumb to T. cruzi
infection compared with WT mice. As T. cruzi mainly affects the heart tissue, we
analyzed the inflammation in this organ. Inflammation in the heart tissue was
very impressive in IL-17R -/- , IL-23 -/- and IL-6 -/- mice, which was important to
control the cardiac parasitism compared with WT mice. Heart inflammation
somewhat promoted cardiac damage in IL-17R -/- , IL-23 -/- and IL-6 -/- mice,
indicated by high CK-MB serum levels. To assess the mechanisms related to
the premature death in the absence of Th17 molecules, we verified that
macrophages from IL-17R -/- , IL-23 -/- and IL-6 -/- mice eliminate the parasite more
efficiently than macrophages from WT mice, by expressing augmented iNOS
and NO levels. We also verified that IL-17R -/- , IL-23 -/- and IL-6 -/- mice induced an
increased, deleterious Th1 response in the heart tissue when compared with
WT mice, indicated by high levels of IFN-γ, IL-12, iNOS and TNF. Corroborating
these data, we detected increased levels of CXCL9 and CXCL10 chemokines
(associated with Th1 migration), but reduced levels of CCR6 (expressed on
Th17 cells), in the heart tissue of IL-17R -/- , IL-23 -/- and IL-6 -/- mice when
compared with WT mice. This intense Th1 response was not efficiently
regulated by anti-inflammatory pathways, as observed by decreased IL-10
levels in the heart of IL-17R -/- , IL-23 -/- and IL-6 -/- mice compared with WT mice.
To confirm the importance of regulatory mechanisms, we observed that WT
mice induced high amounts of regulatory T cells 21 days after infection, the
period that coincide with the death of IL-17R -/- , IL-23 -/- and IL-6 -/- mice,
suggesting that these cells are controlling the local inflammatory response.
Conclusion: Collectively, Th17 cells control myocarditis during T. cruzi