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  • Our ex vivo analysis demonstrates that IL promotes CD


    Our ex vivo analysis demonstrates that IL-15 promotes CD122 expression in DGKζ-deficient CD8+ T cells. CD122, which forms a dimer with CD132 in response to IL-2 or IL-15, activates the JAK/STAT and PI3K/mTOR pathways. Whereas antigen-stimulated ICG-001 promote IL-2 sensitivity through up-regulation of the IL-2Rα chain, IL-15 potentiates self-responsiveness through a positive feedback loop that involves PDK1/mTOR/E4BP4/CD122 signaling (Yang et al., 2015). Our analysis demonstrates enhanced IL-15- induced S6 phosphorylation, the end-point of the mTOR pathway, in DGKζ-deficient CD44hi CD8+ T cells. These results complement our recent observation of DGKζ limiting mTOR activation downstream the TCR (Avila-Flores et al., 2017), and suggest the control by of basal DAG in addition to the lipid generated upon TCR stimulation. Basal DAG levels acting on RasGRP1 is proposed to mediate cytokine-dependent activation of the PDK1/mTOR pathway (Daley et al., 2013a). It is thus tempting to hypothesize that increased basal DAG levels in DGKζ silenced CD8+ T cells facilitates RasGRP1-dependent mTOR activation in response to cytokines. In accordance, the increased proliferation of memory cell subsets induced by IL-15 is mTOR activation-dependent (Richer et al., 2015). All these results support our data and suggest that DGKζ limits a positive feedback loop through which enhanced mTOR activation promotes CD122 induction and IL-2/IL-15 responsiveness. Studies in itk−/− and IL-15−/− mice show that the main functional differences between CD44loCD122lo and CD44hiCD122hi CD8+ T cell populations reside in NK receptor expression (Dubois et al., 2006). Upregulated NK receptors and strong antitumor capacity are also characteristic of CD8+ cells cultured in vitro at high IL-2 or IL-15 concentrations (Dhanji et al., 2004, Dhanji and Teh, 2003). Similar to the known IL-2 effect in overcoming anergy, IL-15 is proposed to overcome immune tolerance and facilitate CD8-mediated tumor destruction (Teague et al., 2006). Using antigen-independent syngeneic xenograft models, we demonstrate that DGKζ-deficient mice develop smaller tumors and reject them more rapidly than WT mice. These data correlate with a recent report of enhanced anti-tumor cytotoxic functions by DGKζ-deficient NK cells (Yang et al., 2016), and suggest a DGKζ role in the control of antigen-independent antitumor functions. Freshly isolated, ex vivo cytokine-treated DGKζ-deficient CD8+ T cells eliminate tumors more rapidly when re-injected into WT mice, suggesting DGKζ negative control of cytokine induction of antitumor cell populations. In agreement with this ability, DGKζ-deficient mice also show increased elimination of other cytokine-sensitive, aggressive tumors (Andrada et al., manuscript in preparation). In summary, our work identifies a distinctive role for DGKζ in limiting IL-2/IL-15-dependent signaling. Our results demonstrate that, in addition to its known role in limiting canonical antigen-mediated activation of cytotoxic function, DGKζ negatively regulates IL-2/IL-15-dependent expansion of innate-like cytotoxic CD8+ T cells. These studies add to the growing evidence that targeting DAG metabolism through pharmacological manipulation of DGKζ could be an important, yet-unexplored area for cancer immunotherapy.
    Funding Sources EA holds a predoctoral fellowship from the Spanish Ministry of Education (AP2010-1370). This work was supported in part by grants from the Spanish Ministry of Economy, Industry and Competitivity and the European Union : MINEICO + FEDER, BFU2013-47640-P and BFU2016-77207-R, the Spanish Ministry of Health (Instituto de Salud Carlos III : RD12/0036/0059) and the Madrid regional government (IMMUNOTHERCAM Consortium S2010/BMD-2326) to IM.
    Author Contributions
    Conflict of Interests