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

CRITICAL ROLE OF IL-6 IN REGULATORY T CELLS DETERMINES THE
OUTCOME OF GUT INFLAMMATION DURING TOXOPLASMA GONDII
INFECTION
MURILO SOLANO-DIAS(1), LUCIANA BENEVIDES(1), MARIA C. SOUZA(1),
GIULIANO BONFÁ(1), RODRIGO R. RODRIGUES(1), BRUNA B. CHAHUD(1),
TIAGO W. P. MINEO(3), ALEXANDRE S. BASSO(2), DENISE M.
FONSECA(1), JOÃO S. SILVA(1)
(1) Department of Biochemistry and Immunology - Ribeirão Preto Medical
School - University of São Paulo - Ribeirão Preto, Brazil; (2) Department of
Microbiology, Immunology and Parasitology, Federal University of São Paulo-
São Paulo – Brazil; (3) Institute of Biomedical Sciences - Federal University of
Uberlândia - Uberlândia – Brazil
Introduction: Recent findings point out for the role of regulatory T cells (Treg)
in the protection against inflammatory diseases induced by parasite infections.
The oral infection with Toxoplasma gondii leads to an intense inflammation in
the gut of susceptible C57BL/6 mice, which succumb to the infection due the
reduction of Treg frequency and suppressive function. Even though the Th1
related cytokines have been associated to this event, it has been reported that
pro-inflammatory cytokines, such as IL-6, might induce the conversion of natural
Tregs in Th17 cells. Therefore, in this study we evaluated the role of IL-6 in the
impairment of Treg during the intestinal inflammation induced by T. gondii.
Methods and Results: Susceptible C57BL/6 and resistant BALB/c mice were
orally infected with 40 cists of T. gondii. Eight days post infection we detected a
significant reduction on CD3+CD4+ Foxp3+ Treg cells in the Lamina Propria,
Peyers Patches and spleens of C57BL/6 mice as compared to BALB/c mice.
The infection compromised mainly the population of induced Treg cells, since
the ratio of induced/natural Tregs (determined by Helios expression) was also
reduced in mesenteric Lymph nodes (LNM) and spleens of C57BL/6 mice,
which also exhibited an increased IL-6 production compared to BALB/c. The
protective role of Tregs were shown by depleting Tregs from resistant mice with
anti-CD25 antibody (PC61). The anti-CD25 treated BALB/c mice became
susceptible to the infection, presented a higher effector/Treg ratio, and
produced a larger amounts of IFN- and IL-6 than non-treated mice. Since
C57BL/6 infected mice produced higher levels of IL-6 than infected BALB/c
mice, we supposed that this cytokine could be involved in the Treg impairment
during the infection. To evaluate this, spleen cells were infected in vitro with T.
gondii and treated with recombinant IL- 6. The in vitro infection reduced the
frequency of Tregs and the addition of IL-6 to the cultures accentuated even
more the impairment of Tregs. Indeed we found that IL-6-/- mice were resistant
to the infection and presented higher Treg frequency and IFN- production in
the LNM and spleens. After the anti-CD25 treatment IL-6-/- mice became