Format

Send to

Choose Destination
Circulation. 2018 Nov 27;138(22):2513-2526. doi: 10.1161/CIRCULATIONAHA.118.034076.

Low-Density Lipoprotein-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice.

Author information

1
Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital (A.G., M.L.K., K.A.P., R.K.W.M., D.F.J.K., G.K.H.), Karolinska Institutet, Stockholm, Sweden.
2
Department of Immunotechnology, Lund University, Sweden (M.L.K.).
3
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (R.K.W.M.).
4
Department of Microbiology, Tumor and Cell Biology (A.D., M.C.I.K.), Karolinska Institutet, Stockholm, Sweden.

Abstract

BACKGROUND:

Atherosclerotic cardiovascular disease is a chronic inflammatory process initiated when cholesterol-carrying low-density lipoprotein (LDL) is retained in the arterial wall. CD4+ T cells, some of which recognize peptide components of LDL as antigen, are recruited to the forming lesion, resulting in T-cell activation. Although these T cells are thought to be proatherogenic, LDL immunization reduces disease in experimental animals. These seemingly contradictory findings have hampered the development of immune-based cardiovascular therapy. The present study was designed to clarify how activation of LDL-reactive T cells impacts on metabolism and vascular pathobiology.

METHODS:

We have developed a T-cell receptor-transgenic mouse model to characterize the effects of immune reactions against LDL. Through adoptive cell transfers and cross-breeding to hypercholesterolemic mice expressing the antigenic human LDL protein apolipoprotein B-100, we evaluate the effects on atherosclerosis.

RESULTS:

A subpopulation of LDL-reactive T cells survived clonal selection in the thymus, developed into T follicular helper cells in lymphoid tissues on antigen recognition, and promoted B-cell activation. This led to production of anti-LDL immunoglobulin G antibodies that enhanced LDL clearance through immune complex formation. Furthermore, the cellular immune response to LDL was associated with increased cholesterol excretion in feces and with reduced vascular inflammation.

CONCLUSIONS:

These data show that anti-LDL immunoreactivity evokes 3 atheroprotective mechanisms: antibody-dependent LDL clearance, increased cholesterol excretion, and reduced vascular inflammation.

KEYWORDS:

T-lymphocytes; apolipoprotein B-100; atherosclerosis; hypercholesterolemia; vaccination

Comment in

PMID:
29997115
PMCID:
PMC6254780
DOI:
10.1161/CIRCULATIONAHA.118.034076
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center