Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity
What this study shows
Activating T cells switch on cholesterol and fatty acid synthesis genes within hours, and this paper showed the switch runs through PI3K and mTOR to SREBP: 100 nM rapamycin given 30 minutes before stimulation blocked the induction of the lipogenic programme, prevented processing of full-length SREBP and its accumulation in the nucleus, and reduced SREBP1 and SREBP2 occupancy at lipogenic promoters to background. Deleting Scap in T cells, which removes both SREBP1 and SREBP2 activity, left thymic and peripheral T-cell numbers normal but the cells could not blast: they entered G1 and stalled, failed to raise cholesterol and fatty acids after activation, and increased ECAR and OCR only modestly where controls rose about ten-fold and four-fold. Adding cholesterol conjugated to methyl-beta-cyclodextrin roughly doubled survival at 48 hours (21 to 45 percent) and restored growth, cell-cycle entry and ER expansion, which points to cholesterol as the limiting step. After LCMV-Armstrong infection the Scap-deficient mice had fewer virus-specific CD8 T cells with lower IFN-gamma and TNF, while homeostatic proliferation was unaffected. Boundary: mouse genetics and mouse cells; the mTOR step is shown with rapamycin pretreatment in cultured T cells, and the in vivo arm measures the consequence of losing SREBP activity rather than of inhibiting mTOR.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse T cells with Cd4-cre-driven deletion of Scap (removing both SREBP1 and SREBP2 activity), siRNA and constitutively active SREBP constructs, rapamycin and LY294002 pretreatment, ChIP for SREBP1/2 at lipogenic promoters, GC-MS lipid measurement, Seahorse profiling, LCMV-Armstrong infection and homeostatic-proliferation transfers) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse T cells with Cd4-cre-driven deletion of Scap (removing both SREBP1 and SREBP2 activity), siRNA and constitutively active SREBP constructs, rapamycin and LY294002 pretreatment, ChIP for SREBP1/2 at lipogenic promoters, GC-MS lipid measurement, Seahorse profiling, LCMV-Armstrong infection and homeostatic-proliferation transfers |
| Journal | Nature Immunology |
| Year | 2013 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/ni.2570 · PMID 23563690 · Free full text (PMC3652626) |
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | T-cell-specific Scap deletion; SREBP1/SREBP2 siRNA; constitutively active SREBP1a/SREBP2; rapamycin 100 nM; LY294002; cholesterol-methyl-beta-cyclodextrin supplementation |
| Target | SREBP processing and the lipogenic gene programme in activated T cells, downstream of PI3K and mTOR |
| Model | Mouse |
| Effect | Loss of SREBP activity blocked T-cell blastogenesis, glycolytic and respiratory reprogramming and antiviral clonal expansion; rapamycin blocked SREBP activation upstream |
In the Atlas
Related topics
Links in the pathway map
More studies on this topic
- Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (2017)
- Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1 (2022)
- Activation of a metabolic gene regulatory network downstream of mTOR complex 1 (2010)
- Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c (2012)
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