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    • Here we sought to characterize

    2018-11-07

    Here we sought to characterize the contribution of DGKα and DGKζ to the generation of non-conventional bystander memory-like CD8+ T cell populations. We show that DGKζ deficiency, but not that of DGKα leads to increased output of CD44hiCD122hi CD8+ T induced pluripotent stem cell and facilitates IL-2 and IL-15 responses. Cytokine-specific expansion of DGKζ-deficient CD44hiCD122hi CD8+ T cells correlates with enhanced anti-tumor effects observed in vivo. Our studies suggest a unique function for DGKζ in the control of innate-like cytotoxic T cell populations, and suggest that pharmacological manipulation of DGKζ activity could be of therapeutic interest for cytokine-directed anti-tumor therapies.
    Material and Methods
    Results
    Discussion Metabolism of DAG by DGKζ phosphorylation is an important mechanism downstream of the TCR that limits T cell responses in naïve T cells. DGKζ deficiency also confers enhanced antitumor potential on pre-activated CD8+ T cells (Riese et al., 2011) and increases the effectiveness of CAR-expressing T cells (Riese et al., 2013). Here we extend these observations by showing that DGKζ deficiency enhances IL-2/IL-15-dependent expansion of cytotoxic CD8+ T cell pools that act in an antigen-independent, innate-like manner. As a result, DGKζ-deficient mice develop smaller tumors when implanted with A20 lymphomas and reject them more rapidly than WT mice. The ability of T lymphocytes to adjust the amount of DAG generated at the membrane to Ras activation intensity is a mechanism that links biological output to TCR affinity for antigen (Roose et al., 2007). This is largely the result of T cells coupling the DAG that is generated in response to TCR-triggered PLCγ activation to the activation of the Ras GEF RasGRP1 (Dower et al., 2000). Enhanced DAG consumption by DGKζ limits RasGRP1 activation downstream the TCR, limiting the intensity of antigen dependent signals. We demonstrate that DGKζ deficiency also leads to heightened sensitivity to the CD122-responsive cytokines IL-2 and IL-15. This observation correlates with impaired IL-2- and IL-15-induced proliferation of CD122hiCD44hi CD8+ T cells in RasGRP1−/− mice, and suggests that enhanced RasGRP1 activation, due to DGKζ deficiency, facilitates cytokine functions. DGKζ dependent control of cytokine functions parallels the reported RasGRP1 role downstream of the common γ chain cytokines in T-cell acute lymphoblastic leukemia, in which high RasGRP1 levels induce cytokine-regulated expansion (Hartzell et al., 2013). The more efficient response of DGKζ-deficient CD8+ T cells to cytokines also fits with the reported ability of this population to expand in a homeostatic manner (Zhong et al., 2003).The presence of CD122hiCD44hi CD8+ T cells in very young DGKζ-deficient mice correlates with its presence in OT-I mice (Riese et al., 2011), and suggests that these cells with a memory-like phenotype arise independently of antigen recognition. DGKζ deficiency correlates with thymic expansion of CD122hiCD44hi CD8+ cells that correlates with enhanced IL-2 thymic production. This expansion in the thymic population correlates with the lack of contraction observed for this population in the periphery, suggesting a causal relationship. Higher affinity of CD122hiCD44hi CD8+ T cells for IL-15 could explain the loss of the naïve CD122loCD44lo CD8+ T cell population. 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 cells 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.