Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1.
Inflammation and cancer are associated with impairment of T-cell responses by a heterogeneous population of myeloid-derived suppressor cells (MDSCs) coexpressing CD11b and GR-1 antigens. MDSCs have been recently implicated in costimulation blockade-induced transplantation tolerance in rats, which was under the control of inducible NO synthase (iNOS). Herein, we describe CD11b+GR-1+MDSC-compatible cells appearing after repetitive injections of lipopolysaccharide (LPS) using a unique mechanism of suppression. These cells suppressed T-cell proliferation and Th1 and Th2 cytokine production in both mixed lymphocyte reaction and polyclonal stimulation assays. Transfer of CD11b+ cells from LPS-treated mice in untreated recipients significantly prolonged skin allograft survival. They produced large amounts of IL-10 and expressed heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with immunoregulatory and cytoprotective properties not previously associated with MDSC activity. HO-1 inhibition by the specific inhibitor, SnPP, completely abolished T-cell suppression and IL-10 production. In contrast, neither iNOS nor arginase 1 inhibition did affect suppression. Importantly, HO-1 inhibition before CD11b+ cell transfer prevented the delay of allograft rejection revealing a new MDSC-associated suppressor mechanism relevant for transplantation.
De Wilde
V
V
Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
Van Rompaey
N
N
Hill
M
M
Lebrun
J F
JF
Lemaître
P
P
Lhommé
F
F
Kubjak
C
C
Vokaer
B
B
Oldenhove
G
G
Charbonnier
L M
LM
Cuturi
M C
MC
Goldman
M
M
Le Moine
A
A
D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D049109:Cell Proliferation; D004731:Endotoxins / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007107:Immune System; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology
D039481:CD11b Antigen; D004731:Endotoxins; C503133:Gr-1 protein, mouse; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D016753:Interleukin-10; D051547:Heme Oxygenase-1