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

TY - JOUR

T1 - IL-18R signaling is required for γδ T cell response and confers resistance to Trypanosoma cruzi infection

AU - da Mota, Julia Barbalho

AU - Echevarria-Lima, Juliana

AU - Kyle-Cezar, Fernanda

AU - Melo, Matheus

AU - Bellio, Maria

AU - Scharfstein, Julio

AU - Oliveira, Ana Carolina

PY - 2020/10/1

Y1 - 2020/10/1

N2 - IFN-γ-producing γδ 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 γδ T cells, playing a role for resistance against infection. We found that splenic γδ+CD3+ cells were rapidly expanded (10–14 days post infection), which was accompanied by an early γδ T cell infiltration into the heart. In the following days, intracardiac parasitism was reduced, the protective immunity being accompanied by decreased γδ T cells tissue infiltration. As predicted, there was a drastic reduction of γδ 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 γδ T cell proliferation. Further characterization revealed that T. cruzi infection up-regulates IL-18R expression in WT γδ+ T cell population whereas Il18r1−/− mice showed impaired generation of cytotoxic GzB+ and IFN-γ-producing γδ T cells. Consistently, in vitro cytotoxicity assay confirmed that cytolytic function was impaired in Il18r1-deficient γδ T cells. As a proof of concept, adoptive transfer of WT γδ 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 γδ T cells response in experimental Trypanosoma cruzi infection.

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

KW - cytotoxicity

KW - IL-18-MyD88 signaling

KW - Trypanosoma cruzi

KW - γδ T cells

UR - http://www.scopus.com/inward/record.url?scp=85085506685&partnerID=8YFLogxK

U2 - 10.1002/JLB.4MA0420-568R

DO - 10.1002/JLB.4MA0420-568R

M3 - Article

C2 - 32450614

AN - SCOPUS:85085506685

SN - 0741-5400

VL - 108

SP - 1239

EP - 1251

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

IS - 4

ER -