Polarization of Chemokine Receptors to the Leading Edge during Lymphocyte Chemotaxis

Abstract

Leukocyte migration in response to cell attractant gradients or chemotaxis is a key phenomenon both in cell movement and in the inflammatory response. Chemokines are quite likely to be the key molecules directing migration of leukocytes that involve cell polarization with generation of specialized cell compartments. The precise mechanism of leukocyte chemoattraction is not known, however. In this study, we demonstrate that the CC chemokine receptors CCR2 and CCR5, but not cytokine receptors such as interleukin (IL)-2Rα, IL-2Rβ, tumor necrosis factor receptor 1, or transforming growth factor βR, are redistributed to a pole in T cells that are migrating in response to chemokines. Immunofluorescence and confocal microscopy studies show that the chemokine receptors concentrate at the leading edge of the cell on the flattened cell-substratum contact area, induced specifically by the signals that trigger cell polarization. The redistribution of chemokine receptors is blocked by pertussis toxin and is dependent on cell adhesion through integrin receptors, which mediate cell migration. Chemokine receptor expression on the leading edge of migrating polarized lymphocytes appears to act as a sensor mechanism for the directed migration of leukocytes through a chemoattractant gradient.

Langerhans cells renew in the skin throughout life under steady-state conditions

“…Because CCR2 is expressed by many cell types that may infiltrate inflamed skin, including macrophages and T cells 29 , the LC deficiency that was detected early after UV-irradiation may reflect a requirement for CCR2 in other hematopoietic cell types involved in LC development. To test whether the requirement for CCR2 was intrinsic to the LC precursor, we followed the reconstitution of mutant and wild-type LCs generated from mixed BM cells (1:1 CCR2 −/− :CCR2 +/+ ) in the same UV-irradiated animals.…”

Chemokines: attractive mediators of the immune response

“…The polarized T cell is already spatially organized in terms of its response to antigen, as the leading edge is more sensitive to CD3 stimulation than the trailing edge, denoting that TCRs are localized to the front edge of the cell [7]. Treatment of T lymphocytes with chemokines or other chemotactic agents leads to the recruitment of CCRs such as CCR2 and CCR5 to this leading edge [8]. Apparently, receptors involved in sensing chemotactic gradients are preferentially localized to the leading edge in a polarized cell.…”

CCR6 Colocalizes with CD18 and Enhances Adhesion to Activated Endothelial Cells in CCR6-Transduced Jurkat T Cells

“…Previous reports have suggested that chemokine receptors on lymphocytes redistribute to the leading edge of polarized migrating cells in response to a soluble, chemotactic ligand (12) and that ligation of chemokine receptors induces the lateral movement of ␤ 2 integrins on lymphocytes (11). Therefore, we hypothesized that chemokine receptors may colocalize with integrins.…”

“…Notably, inhibitors of integrin lateral mobility (i.e., calpeptin) block adhesion of lymphocytes to ICAM-1 at low, but not high, site densities (11). Also, chemokine receptors on T cells polarize in response to ligand and cluster at the leading (migrating) edge of the cell (12), although neutrophils do not show this response and may redistribute intracellular molecules such as the AKT protein kinase to the migrating edge of the cell (13).…”