Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes.

Abstract

SummarySeveral studies have shown that CC chemokines attract T lymphocytes, and that CD45RO +, memory phenotype cells are considered to be the main responders. The results, however, have often been contradictory and the role of lymphocyte activation and proliferation has remained unclear. Using CD45RO + blood lymphocytes cultured under different stimulatory conditions, we have now studied chemotaxis as well as chemokine receptor expression. Expression of the RANTES/MIP-lc~ receptor (CC-CK1K1) and the MCP-1 receptor (CC-CKR2) was highly correlated with migration toward RANTES, MCP-1, and other CC chemokines, and was strictly dependent on the presence of IL-2 in the culture medium. Migration and receptor expression were rapidly downregulated when IL-2 was withdrawn, but were fully restored when IL-2 was added again. The effect oflL-2 could be partially mimicked by IL-4, IL-10, or IL-12, but not by IL-13, IFN',/, IL-1[3, TNF-el, or by exposure to anti-CD3, anti-CD28 or phytohemagglutinin. Activation of fully responsive lymphocytes through the TCP,./CD3 complex and CD28 antigen actually had the opposite effect. It rapidly downregulated receptor expression and consequent migration even in the presence of IL-2. In contrast to the effects on CC chemokine receptors, stimulation ofCD45ILO + T lymphocytes with IL-2 neither induced the expression of the CXC chemokine receptors, IL8-R1 and IL8-P-.2, nor chemotaxis to IL-8. The prominent role of IL-2 in CC chemokine responsiveness of lymphocytes suggests that IL-2-mediated expansion is a prerequisite for the recruitment of antigen-activated T cells into sites of immune and inflammatory reactions. Several chemokines of the CC subfamily are critically involved in the regulation of phagocyte and lymphocyte recruitment in many pathological situations (1, 2). The effects of CC chemokines on monocytes (3-5), basophil, and eosinophil leukocytes (6, 7) are well defined and generally accepted. The situation is more complex for lymphocytes. T lymphocytes were shown to migrate toward RANTES, the macrophage inflammatory proteins MIP-1 ot and MIP-lJ3 (8-10) and, more recently, to respond to the monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3, which are highly effective on CD4 + and CD8 + T cells (11-13). All these CC chemokines induced a transient cytosolic free Ca 2+ rise in T cell clones, which was prevented by B. pertussis toxin (11) suggesting the involvement of G protein-coupled receptors (14). Neither Ca 2+ changes nor chemotaxis, however, were observed in freshly isolated blood lymphocytes, suggesting that activation is necessary.Several chemokine receptors were identified by cloning of their corresponding cDNAs from phagocyte-derived libraries (15)(16)(17)(18)(19)(20)(21)(22). CXC chemokine receptors are expressed primarily in neutrophils (15,16,23), whereas CC chemokine receptors (CC-CKR) 1 are generally found on other leukocytes (17)(18)(19)(20)(21)(22). No corresponding cDNA has been obtained from lymphocytes, however, and little is known about the expression of chemokin...

IFNγ induces functional chemokine receptor expression in human mesangial cells

“…However, with the exception of these studies, there are limited available data regarding the expression and regulation of chemokine receptor expression in tissue cells and resulting chemokine-mediated effects. In leucocytes such as T cells or monocytes, cytokines like IFNg or IL-2 have been reported to modulate the expression of chemokine receptors [22,23]. Unlike our observations in mesangial cells, IFNg selectively down-regulated CCR2 in human monocytes, while CCR1, CCR3, CCR4 and CCR5 were unaffected [23].…”

“…To extend knowledge of the role of chemokines in glomerular inflammation, we investigated the expression of chemokine receptors and their functions in our well established primary human mesangial cell (HMC) culture system [1,7,8,13]. There is evidence that chemokine receptor expression in leucocytes can be regulated by inflammatory signals such as gamma-interferon (IFNg) and interleukins (IL) [22,23]. Since glomerular kidney disease is often characterized by the involvement of T lymphocytes [24], we studied the potential of the prominent T-helper lymphokine IFNg to modulate the expression of chemokine receptors in HMC.…”

Cutting Edge: Human Th17 Cells Are Identified as Bearing CCR2+CCR5− Phenotype

“…Since CCR5 is reported to be expressed predominantly on Th1 cells (16 -18), we hypothesized that SP and DP cells might correspond to Th17 and Th1 cells, respectively. To correlate cytokine production profile and chemokine receptor expression in T cell populations, we first thought of staining total unseparated T cells to detect intracellular cytokines as well as surface CCR; however, the cell activation process required for intracellular cytokine staining was found to down-regulate CCR2 and CCR5 significantly (data not shown), as reported previously (26). To accurately correlate the expression of CCR2 or CCR5 with the cytokine profile ex vivo, we decided to first isolate SP and DP cells from memory CCR2 ϩ T cells by using a flow cytometric cell sorter and stimulate them with PMA and ionomycin.…”

The Primate Lentiviral Receptor Bonzo/STRL33 Is Coordinately Regulated with CCR5 and Its Expression Pattern Is Conserved Between Human and Mouse

“…IL-2 has been described to potently up-regulate CCR1, CCR2, CCR5, CCR6, and CXCR3 (27,30,32,50,51). More recently, IL-15 has been shown to have similar effects on some of the CC chemokine receptors (27,33).…”

“…Cells were stained for Bonzo, CCR5, CCR6, or CXCR4 expression as described in Fig. 4. receptors (27,(32)(33)(34). We asked whether Bonzo is similarly regulated by cytokines on resting human T cells.…”