Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3108-3115 ◽  
Author(s):  
Claudia Carlino ◽  
Helena Stabile ◽  
Stefania Morrone ◽  
Roberta Bulla ◽  
Alessandra Soriani ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nk Cells ◽  
Chemokine Receptor ◽  
Early Pregnancy ◽  
Stromal Cells ◽  
Nk Cell ◽  
Distinct Pattern ◽  
Cell Accumulation ◽  
Decidual Cells ◽  
Uterine Mucosa

Abstract During early pregnancy, uterine mucosa decidualization is accompanied by a drastic enrichment of CD56highCD16− natural killer (NK) cells. Decidual NK (dNK) cells differ from peripheral blood NK (pbNK) cells in several ways, but their origin is still unclear. Our results demonstrate that chemokines present in the uterus can support pbNK cell migration through human endothelial and stromal decidual cells. Notably, we observed that pregnant women's pbNK cells are endowed with higher migratory ability compared with nonpregnant women's or male donors' pbNK cells. Moreover, NK cell migration through decidual stromal cells was increased when progesterone-cultured stromal cells were used as substrate, and this correlated with the ability of progesterone to up-regulate stromal cell chemokine expression. Furthermore, we demonstrate that dNK cells migrate through stromal cells using a distinct pattern of chemokines. Finally, we found that pbNK cells acquire a chemokine receptor pattern similar to that of dNK cells when they contact decidual stromal cells. Collectively these results strongly suggest that pbNK cell recruitment to the uterus contributes to the accumulation of NK cells during early pregnancy; that progesterone plays a crucial role in this event; and that pbNK cells undergo reprogramming of their chemokine receptor profile once exposed to uterine microenvironment.

scholarly journals Impaired NK-cell migration in WAS/XLT patients: role of Cdc42/WASp pathway in the control of chemokine-induced β2 integrin high-affinity state

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2818-2826 ◽  
Author(s):  
Helena Stabile ◽  
Claudia Carlino ◽  
Cinzia Mazza ◽  
Silvia Giliani ◽  
Stefania Morrone ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nk Cells ◽  
Adhesion Molecule ◽  
Chemokine Receptor ◽  
Tyrosine Kinases ◽  
Nk Cell ◽  
Intercellular Adhesion Molecule ◽  
Lymphocyte Function ◽  
Wiskott Aldrich Syndrome ◽  
Β2 Integrin

AbstractWe analyzed the involvement of Wiskott-Aldrich syndrome protein (WASp), a critical regulator of actin cytoskeleton remodeling, in the control of natural killer (NK)–cell migration. NK cells derived from patients with Wiskott-Aldrich syndrome/X-linked thrombocytopenia (WAS/XLT), carrying different mutations in the WASP coding gene, displayed reduced migration through intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), or endothelial cells in response to CXCL12/stromal cell–derived factor-1 and CX3CL1/fractalkine. Inhibition of WAS/XLT NK-cell migration was associated with reduced ability of these cells to up-regulate the expression of CD18 activation neoepitope and to adhere to ICAM-1 or VCAM-1 following chemokine stimulation. Moreover, chemokine receptor or β1 or β2 integrin engagement on NK cells rapidly resulted in Cdc42 activation and WASp tyrosine phosphorylation as well as in WASp association with Fyn and Pyk-2 tyrosine kinases. NK-cell pretreatment with wiskostatin, to prevent Cdc42/WASp association, impaired chemokine-induced NK-cell migration through ICAM-1 and β2 integrin activation-dependent neoepitope expression. These results show that the Cdc42/WASp pathway plays a crucial role in the regulation of NK-cell migration by acting as a critical component of the chemokine-induced inside-out signaling that regulates lymphocyte function–associated antigen-1 function and suggest that after integrin or chemokine receptor engagement WASp function is regulated by the coordinate action of both Cdc42 and tyrosine kinases.

scholarly journals The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β

Reproduction ◽  
2017 ◽  
Vol 154 (6) ◽  
pp. 815-825 ◽  
Author(s):  
Hui-Li Yang ◽  
Wen-Jie Zhou ◽  
Kai-Kai Chang ◽  
Jie Mei ◽  
Li-Qing Huang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Immune Escape ◽  
Nk Cell ◽  
Neutralizing Antibody ◽  
Cell Counting ◽  
Endometrial Stromal Cells ◽  
Cell Behaviors

The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviorsin vitrowere analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor β neutralizing antibody (αhIL-10Rβ) or αTGF-β could partly reverse these effects of ESCs and macrophages on NK cellsin vitro. These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-β, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.

Flt3 Ligand Promotes the Generation of a Distinct CD34+Human Natural Killer Cell Progenitor That Responds to Interleukin-15

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3647-3657 ◽  
Author(s):  
Haixin Yu ◽  
Todd A. Fehniger ◽  
Pascal Fuchshuber ◽  
Karl S. Thiel ◽  
Eric Vivier ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Stromal Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Lower Percentage ◽  
Human Natural Killer Cell ◽  
Flt3 Ligand ◽  
Interleukin 15

Abstract Interleukin-15 (IL-15) is produced by human bone marrow (BM) stromal cells and can induce CD34+ hematopoietic progenitor cells (HPCs) to differentiate into CD56+CD3−natural killer (NK) cells in the absence of stromal cells. IL-15 mediates its effects by signaling through the β and γcchains of the IL-2/15 receptor (R). The c-kit ligand (KL), also produced by stromal cells, enhances the expansion of NK cells from CD34+ HPCs in the presence of IL-15, but alone has no ability to differentiate NK cells. Mice deficient in KL do not appear to have a quantitative deficiency in NK cells, suggesting that other stromal cell factors may contribute to NK cell expansion. Flt3 ligand (FL) is also produced by BM stromal cells and has homology with KL. Furthermore, mice with a targeted disruption of the FL gene have reduced numbers of NK cells. We evaluated here the effects of FL on human NK cell development and expansion from CD34+ HPCs. Like KL, FL significantly enhanced the expansion of NK cells from CD34+ HPCs in the presence of IL-15, compared with IL-15 alone. However, FL alone had no effect on NK cell differentiation. We therefore explored the mechanism by which FL promotes IL-15–mediated NK cell development. FL was found to induce IL-2/15Rβ (CD122) expression on CD34bright HPCs. The CD34brightCD122+ cell coexpressed CD38, but lacked expression of CD7, CD56, NK cell receptors (NKRs), or cytotoxic activity in the absence of IL-15. Using limiting dilution analysis in the presence of IL-15 alone, we demonstrated that the FL-induced CD34brightCD122+ HPCs had an NK cell precursor frequency 20- to 60-fold higher than the CD34dim/negCD122− HPCs and 65- to 235-fold higher than fresh CD34+ HPCs. KL had similar effects as FL, but induced a significantly lower percentage of CD34brightCD122+ cells (P ≤ .01). Both FL and KL also increased IL-15R transcript in CD34+ HPCs. Culture of CD34+ HPCs in FL or KL, followed by culture in IL-15 alone, induced expression of both C-type lectin and Ig-superfamily NKRs on CD56+ cells. These data collectively support a role for FL in early human NK cell development. FL or KL generate a unique CD34brightCD122+CD38+ human NK cell intermediate from CD34+ HPCs that lacks NK features yet is IL-15–responsive. IL-15 is then required for the induction of CD56 and NKRs, LGL morphology, cytotoxic activity, and the ability to produce abundant cytokines and chemokines.

scholarly journals Triggering through CD16 or phorbol esters enhances adhesion of NK cells to laminin via very late antigen 6.

1992 ◽  
Vol 176 (5) ◽  
pp. 1251-1257 ◽  
Author(s):  
A Gismondi ◽  
F Mainiero ◽  
S Morrone ◽  
G Palmieri ◽  
M Piccoli ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Migration ◽  
Nk Cells ◽  
Biochemical Analysis ◽  
Phorbol Esters ◽  
Nk Cell ◽  
Receptor Expression ◽  
Binding Assays ◽  
Binding Domains ◽  
Late Antigen

Very late antigens VLA-1, VLA-2, VLA-3, and VLA-6, belonging to the beta 1 subfamily of integrins, have been identified as receptors for different binding domains of laminin (LM). We have detected VLA-6, but not VLA-1 and VLA-2 on a subset (50-70%) of fresh peripheral blood CD3-, CD16+, CD56+ human natural killer (NK) cells by immunofluorimetric and biochemical analysis. Binding assays performed on LM-coated plates showed that 10-15% of NK cells spontaneously adhere to LM, and this adhesion is mediated by VLA-6. Activation of NK cells through CD16 triggering or by phorbol ester results in a rapid increase of adhesion to LM, which is still mediated by VLA-6. The enhanced adhesiveness is not associated with changes in beta 1 LM receptor expression, while it correlates with changes in the phosphorylation status of alpha 6 subunit. The expression of VLA-6 on NK cells and the modulation of its avidity by activating stimuli may be relevant for NK cell migration and tissue location during inflammation or immune response.

Decidual stromal cells promote the differentiation of CD56 bright CD16 − NK cells by secreting IL‐24 in early pregnancy

2019 ◽  
Vol 81 (6) ◽  
pp. e13110 ◽  
Author(s):  
Hui‐Li Yang ◽  
Wen‐Jie Zhou ◽  
Han Lu ◽  
Sha‐Ting Lei ◽  
Si‐Yao Ha ◽  
...  
Keyword(s):  
Nk Cells ◽  
Early Pregnancy ◽  
Stromal Cells

scholarly journals Engineering lymph node homing of ex vivo–expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5164-5172 ◽  
Author(s):  
Srinivas S. Somanchi ◽  
Anitha Somanchi ◽  
Laurence J. N. Cooper ◽  
Dean A. Lee
Keyword(s):  
Lymph Node ◽  
Nk Cells ◽  
Natural Killer ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Nk Cell ◽  
Ex Vivo ◽  
Ccr7 Expression ◽  
Lymph Node Homing

Natural killer (NK) cells have gained significant attention in adoptive immunotherapy for cancer. Consequently, novel methods of clinical-grade expansion of NK cells have emerged. Subsets of NK cells express a variety of chemokine receptors. However, to expand the scope of adoptively transferred NK cell homing to various malignancies, expression of corresponding chemokine receptors on NK cells is essential. Here, we have explored the use of trogocytosis as a tool to transiently express the chemokine receptor CCR7 on expanded human NK cells with the aim to enhance their homing to lymph nodes. We generated a K562-based “donor” cell line expressing CCR7, Clone9.CCR7, to transfer CCR7 onto NK cells via trogocytosis. CCR7 expression occurred in 80% of expanded NK cells within 1 hour after coculture with Clone9.CCR7. After removal of the donor cells from the coculture, the CCR7 expression on NK cells steadily declined to baseline levels by 72 hours. The acquired CCR7 receptors mediated in vitro migration of NK cells toward CCL19 and CCL21 and increased the lymph node homing by 144% in athymic nude mice. This is the first report on exploiting trogocytosis to rapidly and transiently modify lymphocytes, without direct genetic interven-tion, for adoptive transfer.

IL-15 and IL-2 oppositely regulate expression of the chemokine receptor CX3CR1

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3494-3503 ◽  
Author(s):  
Jana Barlic ◽  
Joan M. Sechler ◽  
Philip M. Murphy
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Chemokine Receptor ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Negative Regulator ◽  
Mouse Bone Marrow ◽  
Primary Mouse ◽  
Receptor Cx3cr1 ◽  
Cx3cr1 Expression

AbstractThe chemokine receptor CX3CR1 (CX3C chemokine receptor 1) is expressed in mouse blood on natural killer (NK) cells and on monocytes. Because interleukin-15 (IL-15) is an essential cytokine for NK cell development and maintenance, we hypothesized that it may induce CX3CR1 expression on this cell type. In contrast, we found that in primary mouse bone marrow-derived NK cells IL-15 specifically inhibited CX3CR1 protein and mRNA accumulation, whereas the related cytokine IL-2 did not inhibit but instead increased CX3CR1 expression. Consistent with this finding, intravenous injection of a single dose of recombinant IL-15 into C57BL/6 mice decreased steady-state CX3CR1 levels 24 hours after injection in freshly isolated peripheral blood mononuclear cells (PBMCs), splenocytes, and bone marrow cells, and treatment of mouse PBMCs with IL-15 in vitro inhibited CX3CL1 (ligand for CX3CR1)-induced chemotaxis. These data suggest that IL-15 may be a negative regulator of innate immunity by inhibiting CX3CR1 expression. These data also suggest that IL-15 inhibition of CX3CR1 may subvert potential cell immunotherapy strategies in which IL-15 is used to expand NK cell populations in vivo or ex vivo. Finally, our results provide additional evidence for differential signaling by IL-2 and IL-15, despite usage of common βγc receptor chains. (Blood. 2003;102:3494-3503)

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