Background-Inflammatory vasculopathies, ranging from the vasculitides (Takayasu arteritis, giant cell arteritis, and polyarteritis nodosa) to atherosclerosis, display remarkable target tissue tropisms for selected vascular beds. Molecular mechanisms directing wall inflammation to restricted anatomic sites within the vascular tree are not understood. We have examined the ability of 6 different human macrovessels (aorta and subclavian, carotid, mesenteric, iliac, and temporal arteries) to initiate innate and adaptive immune responses by comparing pathogen-sensing and T-cellstimulatory capacities. Methods and Results-Gene expression analysis for pathogen-sensing Toll-like receptors (TLRs) 1 to 9 showed vessel-specific profiles, with TLR2 and TLR4 ubiquitously present, TLR7 and TLR9 infrequent, and TLR1, TLR3, TLR5, TLR6, and TLR8 expressed in selective patterns. Experiments with vessel walls stripped of the intimal or adventitial layer identified dendritic cells at the media-adventitia junction as the dominant pathogen sensors. In human artery-severe combined immunodeficiency (SCID) mouse chimeras, adoptively transferred human T cells initiated vessel wall inflammation if wall-embedded dendritic cells were conditioned with TLR ligands. Wall-infiltrating T cells displayed vessel-specific activation profiles with differential production of CD40L, lymphotoxin-␣, and interferon-␥. Vascular bed-specific TLR fingerprints were functionally relevant, as exemplified by differential responsiveness of iliac and subclavian vessels to TLR5 but not TLR4 ligands. Conclusions-Populated by indigenous dendritic cells, medium and large human arteries have immune-sensing and T-cell-stimulatory functions. Each vessel in the macrovascular tree exhibits a distinct TLR profile and supports selective T-cell responses, imposing vessel-specific risk for inflammatory vasculopathies.
Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4+ T cells are selectively activated in the adventitia of affected arteries. In human GCA artery–severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83+ dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia–media border. Adoptive T cell transfer into temporal artery–SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II–matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.
Abstract-CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4 ϩ CD28 Ϫ T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4 ϩ CD28 Ϫ T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4 ϩ CD28 Ϫ IL-12R ϩ cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4 ϩ CD28 Ϫ T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4 ϩ CD28 Ϫ T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4 ϩ CD28 Ϫ T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4ϩ CD28 Ϫ T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions. (Circ Res. 2006;98:524-531.) Key Words: inflammation Ⅲ interleukins Ⅲ cytokines Ⅲ T lymphocyte Ⅲ vascular inflammation T he cellular and biological events causing acute coronary syndrome (ACS) have been linked to the process of plaque rupture and superimposed thrombosis, leading to vessel occlusion and ischemia. 1 Tissue disruption in the atheroma has multiple underlying causes; yet the presence of plaque inflammation is an excellent predictor of vulnerability. 2 Plaque-infiltrating cells are composed of macrophages, dendritic cells (DC), and T cells, all of which contribute to the ultimate outcome of tissue injury. T cells mediate inflammatory damage through 2 pathways: either by regulating the functional activity of macrophages, 3 endothelial cells, and vascular smooth muscle cells or via direct cytotoxicity. 4 Little is known about signals that regulate T-cell recruitment to and retention in the plaque and their functional activity in the nonlymphoid microenvironment of the vessel wall.Plaque-infiltrating T cells are enriched for a particular subset, CD4 ϩ CD28 Ϫ T cells. 5 Such CD4 ϩ CD28 Ϫ T cells are proinflammatory lymphocytes, which produce high amounts of interferon (IFN)-␥ 6 and tumor necrosis factor (TNF)-␣. 7 They also are efficient killer cells, expressing perforin and granzyme B, and lyse endothelial target cells. 8 CD4 ϩ CD28 Ϫ T cells have an unusual chemokine receptor profile, including expression of CX 3 CR1, a receptor typically expressed by NK cells ...
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