TY - JOUR
T1 - The toll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts
AU - Noris, Marina
AU - Cassis, Paola
AU - Azzollini, Nadia
AU - Cavinato, Regiane
AU - Cugini, Daniela
AU - Casiraghi, Federica
AU - Aiello, Sistiana
AU - Solini, Samantha
AU - Cassis, Linda
AU - Mister, Marilena
AU - Todeschini, Marta
AU - Abbate, Mauro
AU - Benigni, Ariela
AU - Trionfini, Piera
AU - Tomasoni, Susanna
AU - Mele, Caterina
AU - Garlanda, Cecilia
AU - Polentarutti, Nadia
AU - Mantovani, Alberto
AU - Remuzzi, Giuseppe
PY - 2009/10/1
Y1 - 2009/10/1
N2 - Members of the TLR/IL-1R superfamily mediate ischemia/reperfusion injury and initiate immune response in transplanted organs. In this study, we tested the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared with naive kidneys. Targeted deletion of Tir8 in the graft exerted a powerful antitolerogenic action leading to acute rejection. Similarly, in a mouse model of kidney graft acceptance induced by costimulation blockade, most Tir8-/- grafts were acutely rejected. Despite similar levels of TLR4, IL-1R, and their ligands, the posttransplant ischemia/reperfusion-induced inflammatory response was more severe in Tir8-/- than in Tir8 +/+ grafts and was followed by expansion and maturation of resident dendritic cell precursors. In vitro, Tir8-/- dendritic cell precursors acquired higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and TNF-α than Tir8+/+ cells, which may explain the increased frequency of antidonor-reactive T cells and the block of regulatory T cell formation in recipients of a Tir8-/- kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the kidney. Tir8 expression and/or signaling in donor tissue are envisaged as a novel target for control of innate immunity and amelioration of graft survival.
AB - Members of the TLR/IL-1R superfamily mediate ischemia/reperfusion injury and initiate immune response in transplanted organs. In this study, we tested the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared with naive kidneys. Targeted deletion of Tir8 in the graft exerted a powerful antitolerogenic action leading to acute rejection. Similarly, in a mouse model of kidney graft acceptance induced by costimulation blockade, most Tir8-/- grafts were acutely rejected. Despite similar levels of TLR4, IL-1R, and their ligands, the posttransplant ischemia/reperfusion-induced inflammatory response was more severe in Tir8-/- than in Tir8 +/+ grafts and was followed by expansion and maturation of resident dendritic cell precursors. In vitro, Tir8-/- dendritic cell precursors acquired higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and TNF-α than Tir8+/+ cells, which may explain the increased frequency of antidonor-reactive T cells and the block of regulatory T cell formation in recipients of a Tir8-/- kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the kidney. Tir8 expression and/or signaling in donor tissue are envisaged as a novel target for control of innate immunity and amelioration of graft survival.
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U2 - 10.4049/jimmunol.0803549
DO - 10.4049/jimmunol.0803549
M3 - Article
C2 - 19734209
AN - SCOPUS:70449709584
VL - 183
SP - 4249
EP - 4260
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -