Skip to main content

Enforcement of T-cell quiescence by Schlafen2

Final Report Summary - SLFN OF T-CELLS (Enforcement of T-cell quiescence by Schlafen2)

Here we are submitting the final report on our research project titles “Enforcement of T-cell quiescence by Schlafen2”. Lymphocyte quiescence is defined as a state of reversible growth arrest in which cells remain responsive to activating stimuli and resistant to cell death. Our recent discovery of a mutant mouse with a defective Slfn2 gene (called ‘elektra’) has enabled us to assign a role for this gene in the maintenance of T lymphocyte quiescence and to further demonstrate that lymphocytes must be actively maintained quiescent to properly differentiate into functional effector cells. However, lymphocyte quiescence is still poorly understood and the mechanism by which Slfn2 maintains it is also unknown.

In the last four years we aimed at finding the mechanism by which Slfn2 maintains quiescence in T cells. We demonstrated that elektra (Slfn2-deficient) T cells display chronic ER stress under steady state conditions. Modulation of ER stress response by depletion of either UPR mediators XBP1 or CHOP improved viability and partially corrected the developmental abnormalities and proliferation capabilities of elektra T cells. Altogether, our results demonstrate a functional connection between Slfn2-induced quiescence in T cells and ER homeostasis, clarifying a novel mechanism by which immune cell quiescence is maintained. These findings are summarized in a manuscript by Omar et al., Oncotarget (2016). Following this study we further demonstrated that the loss of function mutation, elektra, in the quiescence factor Slfn2 leads to accumulation of cholesterol due to increased de novo synthesis in T cells and inflammatory monocytes. Our results establish a potential role for the quiescence factor Slfn2 in maintaining quiescence through regulating sterol homeostasis. These findings are summarized in a manuscript by Omar et al. that is currently under review in Immunology.

In parallel to our work on the mechanism by which Slfn2 enforces quiescence in T-cells we are interested to find out whether we can exploit the elektra phenotype to treat diseases resulting from aberrant T-cell development. For this aim we established mouse models for two human diseases - lympho-proliferative disease and T-cell acute lymphoblastic leukaemia (T-ALL). In this project we demonstrated that the elektra mutation in the T-cell quiescence factor, Slfn2, completely prevents a severe lympho-proliferative disease caused by overexpression of Bcl2 in combination with Fas deficiency in mice. Moreover, we showed that Slfn2 is critical in the pathogenesis of T-ALL induced by activation of the NOTCH1 pathway and that downregulating Slfn2 attenuates the development and the progression of this disease. Overall, our study suggests that targeting Slfn2 holds the potential to constitute a completely novel and ground-breaking strategy for treating T-ALL and other T–cell leukemia/lymphoma. These findings are summarized in a manuscript by Goldshtein et al., Oncotarget (2016).

In addition to this scientific progress I also managed to establish a functional laboratory with diverse expertise that include; cell biology, molecular biology and mouse genetics. My research group includes one MSc. Student, four PhD. students, one postdoc and a technician. Furthermore, I established several collaborations in Israel, Europe and USA with world leading scientists. I recruited several external grants dedicated to the research conducted in my lab, and launched a new course in Immunology for Biomedical Science students in addition to teaching immunology undergraduate pharmacy and life sciences students.