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MTORC1-mediated growth of kidney cysts is rapidly bypassed by other signaling pathways

ABSTRACT: Cystic kidney disease (CyKD) is the leading monogenetic cause of endstage renal disease. In both mice and humans CyKD has been consistently linked to the activation of the mTORC1 pathway. Yet, the utility of mTORC1 inhibitors in CyKD patients remains controversial despite promising preclinical data. To conclusively define the cell intrinsic role of mTORC1 for cyst development, mTORC1 was selectively inactivated in renal tubular cells of an aciliary mouse model of CyKD by deleting the decisive scaffolding protein RAPTOR. Initial preservation of renal function in CyKD∆RAP mice was followed by a steady decline in renal function coinciding with the development of renal cysts in these animals. While overall survival in CyKD∆RAP was considerably prolonged, in-depth transcriptomic analysis showed a rapid activation of other growth-promoting pathways, limiting the effects of mTORC1 deficiency to a relatively small therapeutic window. Future trials in patients with polycystic kidney disease need to acknowledge these findings, and might have to consider combinatorial or sequential therapies to improve efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE58044 | GEO | 2021/07/06

REPOSITORIES: GEO

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Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice

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MTORC1-mediated growth of kidney cysts is rapidly bypassed by other signaling pathways

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