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The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.
- Source :
-
The Journal of cell biology [J Cell Biol] 2022 Nov 07; Vol. 221 (11). Date of Electronic Publication: 2022 Sep 21. - Publication Year :
- 2022
-
Abstract
- Activation of T cells relies on the availability of intracellular cholesterol for an effective response after stimulation. We investigated the contribution of cholesterol derived from extracellular uptake by the low-density lipoprotein (LDL) receptor in the immunometabolic response of T cells. By combining proteomics, gene expression profiling, and immunophenotyping, we described a unique role for cholesterol provided by the LDLR pathway in CD8+ T cell activation. mRNA and protein expression of LDLR was significantly increased in activated CD8+ compared to CD4+ WT T cells, and this resulted in a significant reduction of proliferation and cytokine production (IFNγ, Granzyme B, and Perforin) of CD8+ but not CD4+ T cells from Ldlr -/- mice after in vitro and in vivo stimulation. This effect was the consequence of altered cholesterol routing to the lysosome resulting in a lower mTORC1 activation. Similarly, CD8+ T cells from humans affected by familial hypercholesterolemia (FH) carrying a mutation on the LDLR gene showed reduced activation after an immune challenge.<br /> (© 2022 Bonacina et al.)
- Subjects :
- Animals
Cytokines metabolism
Granzymes metabolism
Humans
Hyperlipoproteinemia Type II
Interferon-gamma metabolism
Mice
Mice, Knockout
Perforin
RNA, Messenger genetics
CD8-Positive T-Lymphocytes metabolism
Cholesterol metabolism
Lymphocyte Activation
Mechanistic Target of Rapamycin Complex 1 genetics
Mechanistic Target of Rapamycin Complex 1 metabolism
Receptors, LDL genetics
Receptors, LDL metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-8140
- Volume :
- 221
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 36129440
- Full Text :
- https://doi.org/10.1083/jcb.202202011