| First Author | Gisterå A | Year | 2018 |
| Journal | Circulation | Volume | 138 |
| Issue | 22 | Pages | 2513-2526 |
| PubMed ID | 29997115 | Mgi Jnum | J:280021 |
| Mgi Id | MGI:6363955 | Doi | 10.1161/CIRCULATIONAHA.118.034076 |
| Citation | Gistera A, et al. (2018) Low-Density Lipoprotein-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice. Circulation 138(22):2513-2526 |
| abstractText | 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. |
