Article

A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature. Blood

Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis 55455, USA.
Blood (Impact Factor: 10.43). 08/2007; 110(2):578-86. DOI: 10.1182/blood-2006-07-036228
Source: PubMed

ABSTRACT How receptor acquisition correlates with the functional maturation of natural killer (NK) cells is poorly understood. We used quantitative real-time polymerase chain reaction (PCR) assays to compare NKG2 and killer immunoglobulin-like receptor (KIR) gene expression in NK cells from allogeneic transplant recipients and their donors. Marked differences were observed in the NK subsets of recipients who had 8-fold more CD56(bright) cells, diminished KIR expression (except 2DL4), and increased NKG2A. In normal blood not all CD56(dim) cells express KIR, and a novel subpopulation of cells committed to the NK-cell lineage was defined. These cells, which comprise 19.4% +/- 2.8% of the CD56(dim) NK population in healthy donors, express the activating NKG2D and NKG2E receptors but no KIR or NKG2A. Although the CD56(dim) NKG2A(-) KIR(-) NK cells lack "at least one" inhibitory receptor for autologous MHC class I, they are not fully responsive, but rather functionally immature cells with poor cytotoxicity and IFN-gamma production. Upon culture with IL-15 and a stromal cell line, CD56(dim) and CD56(bright) KIR(-) NK cells proliferate, express KIR, and develop cytotoxicity and cytokine-producing potential. These findings have implications for the function of NK cells reconstituting after transplantation and support a model for in vivo development in which CD56(bright) cells precede CD56(dim) cells.

Download full-text

Full-text

Available from: Tracy L Bergemann, Aug 26, 2015
0 Followers
 · 
92 Views
  • Source
    • "Expression from individual KIR genes is independently regulated within each NK cell, and during NK cell development, a repertoire of cells is established, in which distinct NK cells stochastically express different members of the KIR family. In order to achieve functional competence, each NK cell must express at least one KIR family member that recognizes at least one of the expressed " self " MHC-I molecules (Anfossi et al., 2006;Cooley et al., 2007). To create further diversity, individuals in the human population inherit different haplotypes of KIR family members (Uhrberg et al., 1997), and most individuals express some KIR that do not recognize their own " self " MHC-I molecules. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Major advances have been made in the field of immunology in the past two decades. A better understanding of the molecular and cellular mechanisms controlling the immune system has opened the door to many innovative and promising new cancer therapies that manipulate the immune response. For instance, toll-like receptor agonists have been shown to boost immune responses toward tumors. Also, a wide array of cell-based immunotherapies utilizing T cells, NK cells, and dendritic cells have been established. Furthermore, a rapidly expanding repertoire of monoclonal antibodies is being developed to treat tumors, and many of the available antibodies have demonstrated impressive clinical responses. Here, we examine some of these immunotherapeutic approaches currently in use or testing to treat cancer, and we examine available evidence with regards to mechanism and efficacy of these treatments.
    European journal of pharmacology 10/2009; 625(1-3):41-54. DOI:10.1016/j.ejphar.2009.09.067 · 2.68 Impact Factor
  • Source
    • "Several investigators have reported that KIR ligand mismatching predicts for donor/recipient allo-reactivity, which reduces leukaemia relapse post-allogeneic PBSCT (Ruggeri et al, 1999, 2002, 2007; Giebel et al, 2003; Morishima et al, 2003; Leung et al, 2004, 2005; Dawson & Spencer, 2005; Elmaagacli et al, 2005; Hsu et al, 2005, 2006; Kroger et al, 2005; Cooley et al, 2007). Others have shown no influence of KIR ligand status, which is probably explained by heterogeneity in transplant procedures, underlying disease and grafts which are either T-replete or vary in extent of T-cell depletion (Davies et al, 2002; Lowe et al, 2003; Bornhauser et al, 2004; Farag et al, 2006; Kroger et al, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Killer immunoglobulin-like receptor (KIR)-ligand mismatched natural killer (NK) cells play a key role in achieving durable remission after haplo-identical transplantation for acute myeloid leukaemia. We investigated the feasibility of transfusing haplo-identical, T-cell depleted, KIR-ligand mismatched NK cells, after conditioning therapy with melphalan and fludarabine, to patients with advanced multiple myeloma (MM) followed by delayed rescue with autologous stem cells. No graft-versus-host disease or failure of autologous stem cells to engraft was observed. There was significant variation in the number of allo-reactive NK cells transfused. However, all NK products containing allo-reactive NK cells killed the NK cell target K562, the MM cell line U266, and recipient MM cells when available. Post NK cell infusion there was a rise in endogenous interleukin-15 accompanied by increasing donor chimaerism. Donor chimaerism was eventually lost, which correlated with the emergence of potent host anti-donor responses indicating that the immunosuppressive properties of the conditioning regimen require further optimization. Further, blocking of inhibitory KIR-ligands with anti-human leucocyte antigen antibody substantially enhanced killing of MM cells thus highlighting the potential for modulating NK/MM cell interaction. Encouragingly, 50% of patients achieved (near) complete remission. These data set the stage for future studies of KIR-ligand mismatched NK cell therapy in the autologous setting.
    British Journal of Haematology 11/2008; 143(5):641-53. DOI:10.1111/j.1365-2141.2008.07340.x · 4.96 Impact Factor
  • Source
Show more