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Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1.

par De Wilde, Virginie ;Van Rompaey, Nicolas ;Hill, M;Lebrun, Jean-François;Lemaitre, Philippe ;Lhommé, Frédéric ;Kubjak, Carole ;Vokaer, Benoît ;Oldenhove, Guillaume ;Charbonnier, Louis-Marie ;Cuturi, M C;Goldman, Michel ;Le Moine, Alain
Référence American Journal of Transplantation, 9, 9, page (2034-2047)
Publication Publié, 2009-09

Article révisé par les pairs

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Résumé :

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.