This increase in energy demand results in increased glucose absorption, which contributes to the promotion of anabolic processes that enables cell growth, proliferation, and the production of effector molecules (Lunt and Vander Heiden, 2011; Chang et al

This increase in energy demand results in increased glucose absorption, which contributes to the promotion of anabolic processes that enables cell growth, proliferation, and the production of effector molecules (Lunt and Vander Heiden, 2011; Chang et al., 2013; Pearce et al., 2013; Peng et al., 2016). Following tissue damage, ATP is released to the extracellular space where it is rapidly hydrolyzed to adenosine by the tandem action of extracellular ectonucleotidases such as CD39 and CD73. a higher commitment to an effector program and are capable of migrating and entering into non-lymphoid peripheral tissues. During T cell effector differentiation, the cells LY2140023 (LY404039) gradually upregulate transcription factors related to effector differentiation, such as T-bet, Blimp-1, and reduce transcription factors related to a less differentiated state such as TCF-7, Lef-1, Bcl-6, among others (Zhang and Bevan, 2011; Kaech and Cui, 2012). The process of effector differentiation is characterized by a metabolic switch necessary to initiate the effector program and functions of cytotoxic T cells (van der Windt and Pearce, 2012; Cammann et al., 2016; Menk et al., 2018). Previous reports indicate that naive lymphocytes have a low energy demand, which they supply through oxidative phosphorylation, mainly through fatty acid oxidation (FAO) and small amounts of glucose to generate ATP (Jones and Thompson, 2007; MacIver et al., 2013). The acquisition of effector features by cytotoxic T cells results from a shift to a predominating glycolytic metabolism in detriment of FAO (Wang et al., 2011; van der Windt and Pearce, 2012; Hukelmann et al., 2016). This increase in energy demand results in increased glucose absorption, which contributes to the promotion of anabolic processes that enables cell growth, proliferation, and the production of effector molecules (Lunt and Vander Heiden, 2011; Chang et al., 2013; Pearce et al., 2013; Peng et al., 2016). LY2140023 (LY404039) Following tissue damage, ATP is released to the extracellular space where it is rapidly hydrolyzed to adenosine by LY2140023 (LY404039) the tandem action of extracellular ectonucleotidases such as CD39 and CD73. The first step LY2140023 (LY404039) in ATP hydrolysis is catalyzed by CD39, which generates ADP and AMP (Robson et al., 2006). The second step involves the action of CD73, which hydrolyzes AMP into adenosine (Regateiro et al., 2013). It has been demonstrated that CD39 and CD73 are highly upregulated in the tumor microenvironment, which causes an increase in the intratumoral concentration of adenosine (reaching the micromolar range). Extracellular adenosine dampens the antitumor response by preventing the activation, proliferation, cytotoxicity, and cytokine production by activating A2A receptor on T cells (Huang et al., 1997; Deaglio et al., 2007; Linnemann et al., 2009; Ohta et al., 2009; Mastelic-Gavillet et al., 2019). The expression of CD39 and CD73 ectonucleotidases was initially described in tumor cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), where they enhance their immunosuppressive function through the production of adenosine (Kobie et al., 2006; Borsellino et al., 2007; Deaglio et al., 2007; Li et al., 2017). However, human and murine CD8+ T cells also express these ectonucleotidases. In humans, naive CD8+ T cells express higher levels of CD73 than CD8+ memory T cells (Dianzani et al., 1993), and activation of PBMC has been reported to induce CD73 and CD39 expression (Dianzani et al., 1993; Raczkowski et al., 2018). In mice, we and others have demonstrated that CD73 is expressed on some T cell subsets, such as na?ve and memory CD8+ T cells, and regulated during terminal effector differentiation (Heng et al., 2008; Flores-Santibanez et al., 2015). Despite this, the role of CD73 and CD73-generated adenosine in the differentiation of CD8+ T lymphocytes is currently unknown. Here we report that CD73 restrains CD8+ T cell differentiation to Tc1 cells leading to reduced cytokine and granzyme B production. In agreement, CD73-deficient cells presented a higher commitment to the effector program with an increased glucose and oxygen consumption rate, indicating that this ectonucleotidase reduces the metabolic fitness in CD8+ T cells. In agreement, NG.1 when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more efficient in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented a.