SREBP1C_FN_CTL · Characterising the role of mammalian Target Of Rapamcyin Complex 1 (mTORC1)/Srebp1c signaling in directing the differentiation and function of T lymphocytes

Characterising the role of mammalian Target Of Rapamcyin Complex 1 (mTORC1)/Srebp1c signaling in directing the differentiation and function of T lymphocytes

The mammalian target of rapamcyin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of natural killer (NK) cells, lymphocytes that play key roles in anti-viral and anti-tumour immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell pro-inflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFNgamma, important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, up-regulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFNgamma production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions. This work was published in Journal of Immunology in 2014 (PMID:25261477) Our on going work is currently further characterising the link between mTORC1 regulated NK cell metabolism and NK cells function and the elucidating molecular mechanisms involved. We have discovered key roles for cMyc and Srebp, but not HIF1alpha, in controlling NK cell glucose metabolism and function. These results are being compiled into 2 manuscripts that will be submitted for consideration at a high impact journals by the end of 2016. Another key objective of this CIG grant was to fully integrate into the research environment at Trinity College Dublin. This objective has been fully realized since the start of this grant. The CIG award has facilitated the establishment of a research group that included 7 PhD students and 1 postdoctoral research scientist. This has been achieved through securing additional funding from national funding agencies. I have published a number of research articles including 2 articles in the Journal of Immunology as senior and corresponding author. I have also been invited to write an number of review articles on the area of immunometabolism for high impact journals including the Journal of Clinical Investigation (5 review articles published, 2015-2016). Therefore, with the help of this Marie Curie Career integration grant I have successfully established a research group in Trinity College Dublin and this research is producing key outputs in the form of research articles in high impact and respected journals.

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