The low-density lipoprotein receptor–mTORC1 axis coordinates CD8+ T cell activation
Fabrizia Bonacina, Annalisa Moregola, Monika Svecla, David Coe, Patrizia Uboldi, Sara Fraire, Simona Beretta, Giangiacomo Beretta, Fabio Pellegatta, Alberico L. Catapano, Federica M. Marelli‐Berg, Giuseppe Danilo Norata
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.