IL-18R signaling is required for γδ T cell response and confers resistance to Trypanosoma cruzi infection

Abstract

IFN-producing 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 T cells, playing a role for resistance against infection. We found that splenic + CD3 + cells were rapidly expanded (10-14 days post infection), which was accompanied by an early T cell infiltration into the heart. In the following days, intracardiac parasitism was reduced, the protective immunity being accompanied by decreased T cells tissue infiltration. As predicted, there was a drastic reduction of 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 T cell proliferation. Further characterization revealed that T. cruzi infection up-regulates IL-18R expression in WT + T cell population whereas Il18r1 −/− mice showed impaired generation of cytotoxic GzB + and IFN-producing T cells. Consistently, in vitro cytotoxicity assay confirmed that cytolytic function was impaired in Il18r1-deficient T cells. As a proof of concept, adoptive transfer of WT 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 T cells response in experimental Trypanosoma cruzi infection.

IL-17A/IFN-γ producing γδ T cell functional dichotomy impacts cutaneous leishmaniasis in mice

“…It has been shown that CD27 + IFNγ-prone γδ T cells expand substantially more than CD27 − IL-17-biased γδ T cells upon adoptive transfer; and the stimulation via the TCR greatly favors IFNγ over IL-17A producers 71,72 ). Previously, γδ T cell transfer was shown to be capable of controlling Trypanosoma infection seemingly through IFN-γ-producing γδ T cells 73 . A similar protection is observed in Toxoplasma infection 74 .…”

Engineering γδ T Cells: Recognizing and Activating on Their Own Way

“…gd T cells also express cytokine receptors, like IL-2Rbg, IL-18R, IL-7Ra, IL23R (107)(108)(109)(110)(111), which can deliver activated signals by binding to interleukins. Stimulation of these cytokine receptors can not only enhance the effect function of gd T cells, but also directly trigger the activation of gd T cells even in the absence of TCR signal.…”

IL-27 maintains cytotoxic Ly6C+ γδ T cells that arise from immature precursors

“…Several molecules and pathways regulate CD27 + IFNγ-producing γδ T cells. Cytokines, including IL-2, IL-12, and IL-15, activate T-bet and EOMES transcription factors to drive expression of IFNγ in these cells (Barros-Martins et al, 2016 ; Chen et al, 2007 ; He et al, 2010 ; Lino et al, 2017 ; Yang et al, 2020 ; Yin et al, 2002 ; Yin et al, 2000 ), while IL-2, IL-15, and IL-18 stimulate their proliferation (Corpuz et al, 2016 ; da Mota et al, 2020 ; Ribot et al, 2012 ). Co-stimulation through CD27 and CD28 augments survival and mitogenic signals for these cells (Ribot et al, 2010 ; Ribot et al, 2012 ).…”