Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice

J Exp Med. 2009 Jan 16;206(1):233-48. doi: 10.1084/jem.20080752. Epub 2009 Jan 12.


Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE(-/-) mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin beta receptor (LTbetaR) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE(-/-) mice with LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Aorta, Abdominal / growth & development*
  • Aorta, Abdominal / metabolism
  • Apolipoproteins E / genetics*
  • Atherosclerosis / genetics
  • Biological Transport
  • Cells, Cultured
  • Chemokine CCL21 / genetics
  • Chemokine CCL21 / metabolism
  • Chemokine CXCL13 / genetics
  • Chemokine CXCL13 / metabolism
  • Cluster Analysis
  • Connective Tissue / growth & development*
  • Connective Tissue / metabolism
  • Gene Expression Profiling
  • In Situ Hybridization
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / metabolism
  • Lymphoid Tissue / cytology
  • Lymphoid Tissue / growth & development
  • Lymphoid Tissue / metabolism
  • Lymphotoxin beta Receptor / antagonists & inhibitors
  • Lymphotoxin beta Receptor / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism
  • Organogenesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Tunica Intima / growth & development
  • Tunica Intima / metabolism
  • Tunica Media / growth & development
  • Tunica Media / metabolism


  • Apolipoproteins E
  • Chemokine CCL21
  • Chemokine CXCL13
  • Cxcl13 protein, mouse
  • Lymphotoxin beta Receptor