The Toll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts.
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-alpha 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.
Noris
Marina
M
Transplant Research Center Chiara Cucchi De Alessandri & Gilberto Crespi, Mario Negri Institute for Pharmacological Research, via Camozzi 3, 24020 Ranica, Bergamo, Italy. noris@marionegri.it
Cassis
Paola
P
Azzollini
Nadia
N
Cavinato
Regiane
R
Cugini
Daniela
D
Casiraghi
Federica
F
Aiello
Sistiana
S
Solini
Samantha
S
Cassis
Linda
L
Mister
Marilena
M
Todeschini
Marta
M
Abbate
Mauro
M
Benigni
Ariela
A
Trionfini
Piera
P
Tomasoni
Susanna
S
Mele
Caterina
C
Garlanda
Cecilia
C
Polentarutti
Nadia
N
Mantovani
Alberto
A
Remuzzi
Giuseppe
G
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D007108:Immune Tolerance / Q000235:genetics; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology
D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C484529:SIGIRR protein, mouse