Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis

Abstract

Tertiary lymphoid organs (TLOs) emerge in tissues in response to non-resolving inflammation such as chronic infection, graft rejection, and autoimmune disease. We identified artery TLOs (ATLOs) in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE−/− mice. ATLOs are structured into T cell areas harboring conventional dendritic cells and monocyte-derived DCs; B cell follicles containing follicular dendritic cells within activated germinal centers; and peripheral niches of plasma cells. ATLOs also show extensive neoangiogenesis, aberrant lymphangiogenesis, and high endothelial venule (HEV) neogenesis. Newly formed conduit networks connect the external lamina of the artery with HEVs in T cell areas. ATLOs recruit and generate lymphocyte subsets with opposing activities including activated CD4+ and CD8+ effector T cells, natural and induced CD4+ T regulatory (nTregs; iTregs) cells as well as B-1 and B-2 cells at different stages of differentiation. These data indicate that ATLOs organize dichotomic innate and adaptive immune responses in atherosclerosis. In this review we discuss the novel concept that dichotomic immune responses toward atherosclerosis-specific antigens are carried out by ATLOs in the adventitia of the arterial wall and that malfunction of the tolerogenic arm of ATLO immunity triggers transition from silent autoimmune reactivity to clinically overt disease.

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

“…ATLO formation in atherosclerosis displays striking similarities with TLO formation in autoimmune diseases. 22,105 The mechanisms underlying TLO neogenesis are in many respects similar to those identified in SLO development during ontogeny although TLO neogenesis requires a chronic inflammatory tissue reaction. In this regard, it is important to note that T-cell effector lymphocytes can be generated in vitro in distinct cytokine environments in the absence of antigen.…”

“…A central tenet of immunity is that primary immune responses are carried out in SLOs, such as LNs, Peyer patches, and spleen, although the possibility that TLOs are also capable of activating naïve lymphocytes in chronic disease states has recently gained attention. 7,[11][12][13][14][15][18][19][20][21][22] After their recruitment to sites where antigen has been deposited, immune cells and the mesenchymal cells of the target tissue generate DC-and lymphocyte-activating cytokines. This inflammatory tissue environment is sensed by sentinel cDCs that initiate the primary immune response.…”

“…37,96 Thus, how tissue inflammation prompts the adaptive immune system to organize T-and B-cell immune responses through danger signal-activated antigen-presenting cells and how tissue inflammation gets out of control are areas of major interest to understand principles of adaptive immunity, autoimmunity, and atherosclerosis. [16][17][18]22,38,39,87,[96][97][98][99][100][101][102] Does ATLO Neogenesis Imply an Atherosclerosis-Specific Autoantigen?…”

Deficiency in Lymphotoxin β Receptor Protects From Atherosclerosis in apoE-Deficient Mice

“…13 However, the pathophysiological role of TLOs in the aorta is currently not completely understood because both, proatherogenic and antiatherogenic lymphocyte populations, have been detected in TLOs. 14 First evidence in humans points to a role of LTbR in atherosclerosis because levels of circulating LTbR in human plasma samples are associated with coronary calcium, aortic plaque, and aortic wall thickness. 15 Therefore, the role of LTbR in atheroprogression and the mechanisms underlying this role remain to be clarified.…”

Lymphocytic tumor necrosis factor receptor superfamily co-stimulatory molecules in the pathogenesis of atherosclerosis

“…T lymphocytes recognize epitopes on the apoB100 unit of native LDL, which supports the production of IgG to oxLDL by B cells [6]. Lymphocytes are also present in aortic tertiary lymphoid organs in very advanced atherosclerosis, in which they are considered to serve as a site for local responses against plaque antigens [7].…”