Anti-IL18R1 polyclonal antibody

IFN-gamma-producing gamma delta T cells have been suggested to play an important role in protection against infection with Trypanosoma cruzi. However, little is known about the mechanisms leading to functional differentiation of this T cell subset in this model. In the current work, we investigated the possibility that the IL-18/MyD88 pathway is central for the generation of effector gamma delta T cells, playing a role for resistance against infection. We found that splenic gamma delta(+)CD3(+) cells were rapidly expanded (10-14 days post infection), which was accompanied by an early gamma delta T cell infiltration into the heart. In the following days, intracardiac parasitism was reduced, the protective immunity being accompanied by decreased gamma delta T cells tissue infiltration. As predicted, there was a drastic reduction of gamma delta T cells in Myd88- and Il18r1-deficient mice, both transgenic strains displaying a susceptible phenotype with increased intracardiac parasitism. In vivo and in vitro assays confirmed that IL-18R deficiency hampered gamma delta T cell proliferation. Further characterization revealed that T. cruzi infection up-regulates IL-18R expression in WT gamma delta(+) T cell population whereas Il18r1(-/-) mice showed impaired generation of cytotoxic GzB(+) and IFN-gamma-producing gamma delta T cells. Consistently, in vitro cytotoxicity assay confirmed that cytolytic function was impaired in Il18r1-deficient gamma delta T cells. As a proof of concept, adoptive transfer of WT gamma delta T cells rescues Il18r1-deficient mice from susceptibility, reducing parasitemia and abrogating the mortality. Collectively, our findings implicate the IL-18R-MyD88 signaling in the mechanisms underlying generation of immunoprotective gamma delta T cells response in experimental Trypanosoma cruzi infection.

Persistent colonization with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes infected individuals to gastric cancer. Conversely, it is also linked to protection from allergic, chronic inflammatory, and autoimmune diseases. We demonstrate here that H. pylori inhibits LPS-induced maturation of DCs and reprograms DCs toward a tolerance-promoting phenotype. Our results showed that DCs exposed to H. pylori in vitro or in vivo failed to induce T cell effector functions. Instead, they efficiently induced expression of the forkhead transcription factor FoxP3, the master regulator of Tregs, in naive T cells. Depletion of DCs in mice infected with H. pylori during the neonatal period was sufficient to break H. pylori-specific tolerance. DC depletion resulted in improved control of the infection but also aggravated T cell-driven immunopathology. Consistent with the mouse data, DCs infiltrating the gastric mucosa of human H. pylori carriers exhibited a semimature DC-SIGN(+)HLA(-)DR(hi)CD80(lo)CD86(lo) phenotype. Mechanistically, the tolerogenic activity of H. pylori-experienced DCs was shown to require IL-18 in vitro and in vivo; DC-derived IL-18 acted directly on T cells to drive their conversion to Tregs. CD4(+)CD25(+) Tregs from infected wild-type mice but not Il18(-/-) or Il18r1(-/-) mice prevented airway inflammation and hyperresponsiveness in an experimental model of asthma. Taken together, our results indicate that tolerogenic reprogramming of DCs ensures the persistence of H. pylori and protects against allergic asthma in a process that requires IL-18.