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

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.

• Authors: Anton Gisterå, Maria L Klement, Konstantinos A Polyzos, Reiner K W Mailer, Amanda Duhlin, Mikael C I Karlsson, Daniel F J Ketelhuth, Göran K Hansson
• Journal: Circulation (Circulation) Vol. 138 Issue 22 Pg. 2513-2526 (11 27 2018) ISSN: 1524-4539 [Electronic] United States
• PMID: 29997115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Apolipoprotein B-100
• Apolipoproteins E
• Lipoproteins, LDL
• Receptors, Antigen, T-Cell
• Cholesterol

Topics

• Animals
• Antibodies (immunology)
• Apolipoprotein B-100 (blood)
• Apolipoproteins E
• Atherosclerosis (pathology, prevention & control)
• B-Lymphocytes (cytology, immunology, metabolism)
• CD4-Positive T-Lymphocytes (cytology, immunology, metabolism)
• Cholesterol (blood)
• Disease Models, Animal
• Lipoproteins, LDL (administration & dosage, immunology)
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Receptors, Antigen, T-Cell (genetics, metabolism)