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

CRUCIAL ROLE OF REGULATORY T CELLS IN THE IL-17- AND IL22-
MEDIATED CONTROL OF INTESTINAL INFLAMMATION
DENISE MORAIS DA FONSECA(1); LUCIANA BENEVIDES(1); MARIA DO
CARMO SOUZA(1); GIULIANO BONFÁ(1); MURILO SOLANO-DIAS(1); TIAGO
W. P. MINEO(2); BERNHARD RYFFEL(3); ALEXANDRE SALGADO
BASSO(4); JOÃO SANTANA DA SILVA(1)
(1)Department of Biochemistry and Immunology - Ribeirão Preto Medical
School - University of São Paulo - Ribeirão Preto, Brazil; (2)Institute of
Biomedical Sciences - Federal University of Uberlândia - Uberlândia - Brazil;
(3)Centre National de la Resarche Scientifique, Immunologie et Embryologie
Moléculaire – University of Orléans - Orléans – France; (4)Department of
Microbiology, Immunology and Parasitology, Federal University of São Paulo-
São Paulo – Brazil
Introduction: Understanding the mechanisms involved in the control of
mucosal inflammation in diseases established after the breakdown of intestinal
tolerance is one of the biggest challenges for science nowadays. In the gut
inflammation induced after T. gondii infection, the relative importance of each
individual Th1, Th17 and regulatory T (Treg) cells has been partially
investigated. However, the main question that remains is whether these cells
interact and work together to regulate the intestinal immune-mediated disease.
Here we determined how Th17, Th22 and Treg cells contribute to intestinal
homeostasis after T. gondii infection. Methods and Results: We found that
C57BL/6-susceptible and BALB/c-resistant mice (orally infected with T. gondii)
exhibited a progressive increase on the frequencies of Th17 and Th22 cells in
Lamina Propria and Peyer´s patches. However, whereas C57BL/6 mice showed
higher frequency of Th17, BALB/c mice showed higher counts of Th22 and Treg
cells. There was higher frequency of induced-Tregs (Foxp3+Helios-) in BALB/c
mice, on contrary to C57BL/6 mice in which these cells were almost absent.
The ratio between Tregs/Effector cells was significantly increased in C57BL/6
mice and the infection impaired the effector function of Tregs in susceptible
hosts. Tregs obtained from C57BL/6-infected mice, but not from BALB/c,
showed reduced expression of GITR, CTLA-4, increased PDL1 and reduced
suppressive activity in vitro. The transfer of Foxp3+ cells sorted from noninfected
mice, but not from infected mice, increased C57BL/6 recipient survival.
In vitro infected spleen cells experiments showed that Tregs impairment was
related to the presence of IFN- , IL-6 and IL-17, but IL-2, IL-22 and TGF-
were responsible for Treg maintenance. Because of this, we evaluated the role
of IL-17 and IL-22 in the disease and we observed that IL-17R-/- and IL-22-/-
mice were more susceptible, presented higher parasite burden and intestinal
inflammation; and lower Treg frequency than C57BL/6. The transfer of Th17
cells increased C57BL/6 mice survival and transfer of Treg cells restored IL-
17R-/- and IL-22-/- mice resistance. Conclusion: Taken together, these