When 3 × 106 WT (CD39+/+), but not CD39−/− liver mDCs, were infused into the CD39−/− liver grafts, the extent of liver IRI was reduced significantly (Fig. 7). These data demonstrate that CD39 on liver mDCs can protect against LT I/R injury. Given their high rate of constitutive exposure to dietary antigens and MAMPs, it is important that liver DCs maintain a tolerogenic state under normal physiological conditions to avoid inflammation.[3] Several mechanisms have been proposed to restrain conventional liver mDC activation and maturation Venetoclax research buy that may also contribute to their inherent tolerogenicity. These include expression of negative regulators

of TLR signaling[7] as well as production of IL-10.[4, 7] Here, we show, for the first time, that resistance of mouse liver mDCs to maturation induced by ATP is associated with significantly higher constitutive levels of CD39 on these cells, compared with mDCs from secondary lymphoid tissue or kidney. To what extent expression of CD39 in the cis or trans position might govern the responsiveness of the entire DC population in these tissues was not investigated. The higher levels of cell-surface CD39 on liver mDCs correlated Protein Tyrosine Kinase inhibitor with the

superior ability of these DCs to hydrolyze ATP, a property that was absent from CD39−/− liver mDCs. Our findings also show that the enhanced cold I/R injury and systemic inflammation observed after OLT from CD39−/−, compared to WT donors, is associated with increased activation and maturation of liver interstitial mDCs. Moreover, WT, but not CD39−/−, liver mDCs exerted a protective effect against transplant-induced liver IRI when adoptively transferred to CD39−/− liver grafts, implicating CD39 expression on liver mDCs in the regulation Leukocyte receptor tyrosine kinase of liver transplant IRI. Innate immune cells, such as natural killer (NK) cells or DCs, respond acutely in injury models by virtue of inherent cytotoxic

properties and/or release of cytokines. Recently, deletion of CD39, the dominant ectonucleotidase on NK cells, has been shown to attenuate partial warm liver IRI,[38] whereas adoptive cell transfer studies have supported a role of CD39 on NK cells in liver injury.[38] Studies on NKT cells (that express both CD39 and CD73) have suggested a role for purinergic signaling in NKT cell-mediated mechanisms that result in liver immune injury.[39] Activated NKT cells appear to be important in warm hepatic IRI,[40] although less so in cold liver IRI.[24] Thus, it seems unlikely that NKT cells contributed in any major way to the enhanced liver damage associated with CD39 deficiency in the present LT IRI studies. Pommey et al.[24] have shown that mice that overexpress CD39 exhibit CD4+ T-cell lymphopenia and impaired CD4+ T-cell function that afford protection against liver IRI. Here, we found that CD4+ and CD8+ T-cell number and function were preserved in CD39−/− mice.