Tertiary lymphoid organs (TLOs) emerge during nonresolving peripheral inflammation, but their impact on disease progression remains unknown. We have found in aged Apoe(-/-) mice that artery TLOs (ATLOs) controlled highly territorialized aorta T cell responses. ATLOs promoted T cell recruitment, primed CD4(+) T cells, generated CD4(+), CD8(+), T regulatory (Treg) effector and central memory cells, converted naive CD4(+) T cells into induced Treg cells, and presented antigen by an unusual set of dendritic cells and B cells. Meanwhile, vascular smooth muscle cell lymphotoxin β receptors (VSMC-LTβRs) protected against atherosclerosis by maintaining structure, cellularity, and size of ATLOs though VSMC-LTβRs did not affect secondary lymphoid organs: Atherosclerosis was markedly exacerbated in Apoe(-/-)Ltbr(-/-) and to a similar extent in aged Apoe(-/-)Ltbr(fl/fl)Tagln-cre mice. These data support the conclusion that the immune system employs ATLOs to organize aorta T cell homeostasis during aging and that VSMC-LTβRs participate in atherosclerosis protection via ATLOs.

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.

Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr^−/− mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5^−/− or Il13^−/− ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.