Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

Abstract

Tertiary lymphoid organs emerge in tissues in response to nonresolving inflammation. Recent research characterized artery tertiary lymphoid organs in the aorta adventitia of aged apolipoprotein E–deficient mice. The atherosclerosis-associated lymphocyte aggregates are organized into distinct compartments, including separate T-cell areas harboring conventional, monocyte-derived, lymphoid, and plasmacytoid dendritic cells, as well as activated T-cell effectors and memory cells; B-cell follicles containing follicular dendritic cells in activated germinal centers; and peripheral niches of plasma cells. Artery tertiary lymphoid organs show marked neoangiogenesis, aberrant lymphangiogenesis, and extensive induction of high endothelial venules. Moreover, newly formed lymph node–like conduits connect the external lamina with high endothelial venules in T-cell areas and also extend into germinal centers. Mouse artery tertiary lymphoid organs recruit large numbers of naïve T cells and harbor lymphocyte subsets with opposing activities, including CD4 + and CD8 + effector and memory T cells, natural and induced CD4 + regulatory T cells, and memory B cells at different stages of differentiation. These data suggest that artery tertiary lymphoid organs participate in primary immune responses and organize T- and B-cell autoimmune responses in advanced atherosclerosis. In this review, we discuss the novel concept that pro- and antiatherogenic immune responses toward unknown arterial wall–derived autoantigens may be organized by artery tertiary lymphoid organs and that disruption of the balance between pro- and antiatherogenic immune cell subsets may trigger clinically overt atherosclerosis.

Adaptive Response of T and B Cells in Atherosclerosis

“…In mice, these lymphoid-like structures have been shown to harbor large numbers of T cells, ie, naive, effector/memory, cytotoxic T cells, Tregs, and B cells at various stages of differentiation, indicating that the activation of T and B cells in the vessel wall may occur within ATLOs, in addition to plaques, which could be associated to disease in some cases. 6,15,16 Still debated, the presence of ATLOs have been recently suggested to confer protection against advanced atherosclerosis in an age-and site-specific manner. 17 Whether these structures should be considered a passive bystander of tissue inflammation or active players in disease requires further analysis.…”

“…However, larger number of B cells may be found in the adventitial layer of the arterial wall, where tertiary lymphoid organs can be formed. 6 T and B cells have been proposed to be key modulators of atherogenesis and plaque stability.…”

Reduced T-Cell Thymic Export Reflected by sj-TREC in Patients with Coronary Artery Disease

“…Quantification of sj-TREC was performed by SYBR Green real-time quantitative PCR in Bio-Rad CFX Connect (Bio-Rad laboratories, Foster city, USA) as described previously 11,34) . Reaction mixtures conplaque rupture 5,6) . Unstable plaques are characterized by the activation and infiltration of circulating effector T cells with specificity for both autologous and external antigens 7,8) .…”

Targeting B Cells in Atherosclerosis

“…In cases of chronic inflammation such as atherosclerosis, tertiary lymphoid organs develop adjacent to diseased tissue, the arterial adventitia in the case of atherosclerosis, and may become major sites of adaptive immune activation. [18][19][20] It is likely that tertiary lymphoid organs accumulate B cells with relevant antigen specificity, 21 or B-cell subsets that exhibit specific properties, for example, circulating capacity. 22 The workload of responding to different antigens is divided between different B-cell subsets.…”