Vascular dendritic cells in giant cell arteritis.
Giant cell arteritis (GCA) is a granulomatous vasculitis that selectively targets medium-sized and large arteries, especially the cranial branches of the aorta. The inflammatory activity of vascular lesions is driven by adaptive immune responses, with CD4 T cells undergoing clonal expansion in the vessel wall and releasing interferon gamma. Recent studies have described a distinctive population of dendritic cells (DCs) localized at the adventitia-media border of normal medium-sized arteries that appear to play a critical role in the initiation of vasculitis. Immune effector functions of this DC population are being examined in human artery-severe combined immunodeficient (SCID) mouse chimeras. In their constitutive form, CD11c+ fascin+ adventitial DCs are not recognized by alloreactive T cells. Triggering with Toll-like receptor (TLR) ligands is sufficient to break this state of tolerance and initiate DC activation, T-cell recruitment, T-cell activation, and T-cell retention in the arterial wall. Systemic administration of ligands for TLR2 or -4 in human artery-SCID chimeras drives differentiation of adventitial DCs into chemokine-producing effector cells with high-level expression of both CD83 and CD86 and mediates T-cell regulatory function through release of interleukin 18. In established vasculitis, fully matured DCs retain antigen-presenting function; antibody-mediated DC depletion disrupts T-cell and macrophage activation and has marked anti-inflammatory effects. We conclude that adventitial DCs, an indigenous cell population of the arterial wall, are responsive to pathogen-derived macromolecules and have gatekeeper function in regulating T-cell recruitment and retention to the arterial adventitia. A switch of adventitial DCs from being nonstimulatory to T-cell activating emerges as a critical event in the initiation of vasculitis.
Weyand
Cornelia M
CM
Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Rm. 1003, Woodruff Memorial Research Bldg., 101 Woodruff Cir., Atlanta, GA 30322, USA. cweyand@emory.edu
Ma-Krupa
Wei
W
Pryshchep
Olga
O
Gröschel
Stefan
S
Bernardino
Roberto
R
Goronzy
Jörg J
JJ
D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology*; D013700:Giant Cell Arteritis / Q000097:blood / Q000276:immunology / Q000473:pathology; D006801:Humans