Artery Tertiary Lymphoid Organs Control Aorta Immunity and Protect against Atherosclerosis via Vascular Smooth Muscle Cell Lymphotoxin β Receptors

Abstract

SummaryTertiary 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−/−Ltbrfl/flTagln-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.

Adaptive Response of T and B Cells in Atherosclerosis

“…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.…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Although lymphoid neogenesis is typically associated with exacerbation of chronic inflammatory processes, a recent study demonstrates a protective role for ELFs in atherosclerosis 107. ELFs develop in the aorta of aged Apoe −/− mice where they correlate with disease severity 123.…”

“…ELFs develop in the aorta of aged Apoe −/− mice where they correlate with disease severity 123. These structures were typically located adjacent to atherosclerotic plaques where they control immune cell trafficking, antigen presentation and T‐cell priming and differentiation 107. Hence, aortic ELFs may play an important role in establishing local T‐cell immunity during ageing in atherosclerosis.…”

New insights into the pathogenesis of giant cell arteritis

“…This immune-privilege is lost with age as demonstrated by the presence, in elderly people and in advanced atherosclerotic lesions, of adventitial lymphoid infiltrates ranging from tight clusters of B cells and T cells to highly organized structures sometimes comprising functional germinal centres, the socalled artery tertiary lymphoid organs, ATLOs [55]. Tertiary lymphoid organs (TLOs) develop at sites of inflammation where they influence the course of infection and autoimmune diseases [56].…”