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.

The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation / F. Bonacina, A. Moregola, M. Svecla, D. Coe, P. Uboldi, S. Fraire, S. Beretta, G. Beretta, F. Pellegatta, A.L. Catapano, F.M. Marelli-Berg, G.D. Norata. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 221:11(2022 Nov 07), pp. e202202011.1-e202202011.26. [10.1083/jcb.202202011]

The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation

F. Bonacina
Co-primo
;
A. Moregola
Co-primo
;
M. Svecla;P. Uboldi;G. Beretta;G.D. Norata
Ultimo
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.
Animals; Cytokines; Granzymes; Humans; Hyperlipoproteinemia Type II; Interferon-gamma; Mice; Mice, Knockout; Perforin; RNA, Messenger; CD8-Positive T-Lymphocytes; Cholesterol; Lymphocyte Activation; Mechanistic Target of Rapamycin Complex 1; Receptors, LDL
Settore BIO/14 - Farmacologia
PRIN201719GNORA_01 - Integrating metabolism and immunity: cellular and molecular pathways leading to metabolic dysregulation and autoimmunity - NORATA, GIUSEPPE DANILO - PRIN2017 - PRIN bando 2017 - 2019
PRIN201719ACATA_01 - Low density lipoprotein receptor (LDLR)-independent effects of proprotein convertase subtilisin/kexin type 9 (PCSK9): role in modulating insulin-resistance, ectopic fat accumulation and low-grade inflammation - CATAPANO, ALBERICO LUIGI - PRIN2017 - PRIN bando 2017 - 2019
MIS21GNORA_01 - Improving diagnosis and therapy for familial dyslipidaemias: a network of general practitioners and specialised lipid centers - NORATA, GIUSEPPE DANILO - MIS - Bandi Ministero Salute - 2021
CAR_RIC20FBONA_01 - Molecular mechanisms of T regulatory impairment in Familial Hypercholesterolemia: exploring cellular metabolic reprogramming as a tool to restore theirsuppressive function - BONACINA, FABRIZIA - CAR_RIC - Bandi Fondazione Cariplo - 2020
21-set-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/944812
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