Plasmacytoid Dendritic Cell Recruitment by Immobilized CXCR3 Ligands

Abstract

Plasmacytoid dendritic cells (pDCs) recognize microbes, viruses in particular, and provide unique means of innate defense against them. The mechanism of pDC tissue recruitment remained enigmatic because the ligands of CXCR3, the cardinal chemokine receptor on pDCs, have failed to induce in vitro chemotaxis of pDCs in the absence of additional chemokines. In this study, we demonstrate that CXCR3 is sufficient to induce pDC migration, however, by a migratory mechanism that amalgamates the features of haptotaxis and chemorepulsion. To mediate “haptorepulsion” of pDCs, CXCR3 requires the encounter of its cognate ligands immobilized, optimally by heparan sulfate, in a form of a negative gradient. This is the first report of the absolute requirement of chemokine immobilization and presentation for its in vitro promigratory activity. The paradigmatic example of pDC haptorepulsion described here may represent a new pathophysiologically relevant migratory mechanism potentially used by other cells in response to other chemokines.

Plasmacytoid Dendritic Cells Migrate in Afferent Skin Lymph

“…Indeed in L-selectindeficient mice, pDC numbers were reduced by 85% in lymph nodes (52), suggesting pDC extravasation via high endothelial venule. However, mouse pDC exposure to HSV up-regulated a CCR7-dependent migration in vitro; in addition, pDC were occasionally found close to lymph vessels in HSV-induced lesions, suggesting that a CCR-7-mediated lymph migration may occur (53). Expression of CCR7 has also been demonstrated on human pDC (54) and it could be involved in pDC trafficking in lymph due to CCL19/CCL21 production by lymphatic endothelial cells (55).…”

Simian Immunodeficiency Virus Infection Alters Chemokine Networks in Lung Tissues of Cynomolgus Macaques

“…CXCR3 is expressed on activated T-lymphocytes, particularly type-1 T cells, 35 activated natural killer cells, 36 and plasmacytoid DCs. 37 Inflammatory reactions comprised of increased CXCR3 ligand expression are therefore complex and involve both innate and adaptive immune responses in the lungs. These chemokines induce migration of CXCR3 ϩ T cells from the blood through the blood vascular endothelium into the pulmonary interstitium, and then into the alveolar spaces.…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…This hypothesis was subsequently confirmed, in the mouse. Indeed, PDCs express lymph node homing molecules such as L-selectin and PSGL1, the counter-ligand of P-and E-selectins [33,34]. In addition, PDCs express CXCR4, the receptor for CXCL12, which is a homeostatic chemokine expressed by HEV [3,33,[35][36][37].…”

“…Indeed, PDCs express lymph node homing molecules such as L-selectin and PSGL1, the counter-ligand of P-and E-selectins [33,34]. In addition, PDCs express CXCR4, the receptor for CXCL12, which is a homeostatic chemokine expressed by HEV [3,33,[35][36][37]. Lselectin and CXCL12 are apparently central in inducing PDCs migration, as shown by the reduced number of PDCs in the secondary lymphoid organs of mice defective for Lselectin and DOCK2, a molecule involved in CXCR4 signalling in PDCs [34,38].…”

“…31 No.7 are fully competent in inducing PDCs adhesion and migration when immobilized on heparan sulphates expressed by endothelial cells [33]. Two recent reports showed that PDCs purified from patients with chronic hepatitis C, or exposed in vitro to IFN-a, acquire the ability to respond to CCR2, CCR5 and CXCR3 ligands [44,45].…”