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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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