Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice

Abstract

IntroductionHuman natural killer (NK) cells are predominantly large granular lymphocytes (LGLs), the majority of which express CD16 and CD56 cell-surface antigens. A small subset of NK cells lacks CD16 and expresses high levels of CD56 and CD94. Another major CD56 ϩ population is composed of T cells that express the CD3 antigen. The human peripheral blood lymphocyte (PBL) NK T-cell population is enriched with CD8 ϩ T cells of effector phenotypes. NK and NK T cells can mediate cytolysis of tumor cells and virus-infected cells. 1,2 To improve responses against metastatic tumors, a variety of adoptive cellular strategies have been tested. Among the techniques most studied and developed is the use of lymphokine-activated killer (LAK) cells. LAK cells express surface markers characteristic of NK cells, including CD56 and CD16, and rarely express the common T-cell marker CD3. 3,4 The LAK activity is induced from a population of resting lymphoid cells by in vitro exposure of these cells to a supraphysiologic concentration of IL-2 (500-1000 IU/mL). 3,4 NK and NK T cells are also key effector cells mediating the graft-versus-leukemia (GVL) effect, which is used to control minimal residual disease (MRD) and for the reinduction of remission in chronic myelogenous leukemia patients who relapse after allogeneic stem cell transplantation. 1,[5][6][7][8] These cells are also important for low-intensity conditions and nonmyeloablative allogeneic stem cell transplantation, which are currently being performed not only in hematologic malignancies, but also in solid tumors such as renal cell carcinoma. 9 In hematogenic metastasis, such as that of prostate cancer, breast cancer, and neuroblastoma, the malignant cells home, arrest, and develop in the BM. 10,11 In order to extract their function, NK and NK T cells must reach the BM. However, the mechanism that regulates the trafficking of these cells to the BM is unknown.Chemokines and their receptors have an essential role in the recruitment and tissue localization of cells from the immune system. 12 NK cells have mainly been reported to express chemokine receptors from the CXC family, such as CXCR1-4 and CXC3R1. In contrast, CD56 ϩ , CD16 Ϫ , CD3 ϩ NK T cells have been shown to express the chemokine receptors CCR1, CCR2, CCR5, and CCR6 from the CC family and the chemokine receptors CXCR 3, CXCR4, and CXCR6 from the CXC family. 13,14 The chemokine receptor CXCR4 and its ligand, CXCL12, have been shown to play a crucial role in the trafficking and tissue localization of human hematopoietic stem cells and breast tumor cells to hematopoietic organs. 15,16 This makes the chemokine-receptor pair CXCL12/CXCR4 of particular interest in investigating their own role in the homing of NK and NK T cells to the BM microenvironment. Here we show that the homing of NK and NK T cells to the BM was dependent upon G protein signaling and CXCR4 and was inhibited by IL-2 treatment. Upon activation of these cells with IL-2, CXCR4 expression was reduced, whereas the expression of CXCR3 on the cell surface...

Evaluation of ex vivo expanded human NK cells on antileukemia activity in SCID-beige mice

“…Our data confirmed previous observations with in vitro IL-2 activated NK cells, that is, a tendency of these cells to migrate towards the liver and inflammatory areas. 33,34 In addition, we also detected CD56 þ human effector cells in the blood and bone marrow of the mice. These observations are in line with a recent study investigating NK cell distribution in renal cell carcinoma patients.…”

Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

“…We observed complementary findings in that liver-derived T, NKT and NK cells express high levels of CXCR4. Several reports have indicated down-regulation of CXCR4 upon activation of T, NKT and NK cells [38,39]. The high expression levels of CXCR4 on LIL in the chronically inflamed liver may result from the induction of CXCR4 by TGF-g .…”

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

“…We therefore used the conditioned medium of immature or LPS-stimulated mature DCs in the lower chamber of the trans-well system to examine the migration of the IL-2-activated NK cells. We used also CXCL12, a chemokine previously studied in the trans-well assay [41], as a positive control. In consistent with the results we observed in the microfluidic system, we found that both of the conditioned media of the LPS-stimulated mature and immature DCs induced a statistically significant (*p < 0.05) recruitment of NK cells into the lower chamber of the trans-well system (Fig.…”