This study evaluated whether T-cell memory reflects increased precursor frequencies of specific long-lived

IntroductionImproved outcome of acute myeloid leukemia (AML) after stemcell transplantation across the human leukocyte antigen (HLA) class I barrier highlighted a potential of natural killer (NK) cells in recognition and elimination of residual malignant cells by the graft-versus-leukemia (GVL) effect in the absence of graft-versushost disease (GVHD). 1,2 NK cells develop rapidly from transplanted progenitor cells but display numerous phenotypic abnormalities and a functional immaturity, which may limit their effectiveness in tumor rejection in vivo. 3,4 Adoptive transfer of mature NK cells in the early posttransplantation period is therefore a rational approach aimed at providing the patient with the benefit of competent cytotoxic effectors. 5 NK cells are innate immunity CD56 ϩ CD3 Ϫ lymphocytes, the function of which is regulated by the integration of signals delivered from multiple inhibitory and activating receptors. 6 The killer immunoglobulin-like receptors (KIRs), which are clonally distributed in the NK-cell repertoire, recognize allelic groups of HLA class I molecules on target cells and are dominant determinants of NK-cell function. 7 NK cytotoxicity is inhibited on recognition of "self" HLA class I molecules, whereas absence or loss of HLA class I can render cells susceptible to NK-mediated lysis. In the transplant setting from haploidentical stem-cell donor, alloreactivity of NK cells is provided by the KIR-HLA class I mismatch. 8 In addition to sensing the missing self HLA class I molecules, NK cells need to be stimulated through engagement of activating NK receptors by specific cell-surface ligands expressed by target cells. 9,10 NKG2D is one of the best characterized receptors required for NK-mediated tumor immunosurveillance. 11 In mice, NKG2D function can protect the host from tumor initiation and also eradicate existing tumors expressing the H60 and Rae-1 ligands. 12,13 The human NKG2D ligands (NKG2D-L) include 2 families of proteins belonging to major histocompatibility complex class I (MIC)-related molecules, and UL-16 binding proteins (ULBP). 14,15 In epithelial tissue, the surface expression of NKG2D-L is up-regulated in response to cellular stress, including heat shock, DNA damage, and stalled DNA replication, which are common in human cancer. 16,17 A notion that NKG2D-L play a key role as tumor-associated ligands rendering cells susceptible to NK-mediated lysis, has encouraged pharmacologic approaches to achieve the NKG2D-L induction. 18,19 Understanding the molecular interactions regulating the NK function has uncovered numerous escape mechanisms preventing recognition of leukemic blasts by NK cells. Unlike in solid tumors, which frequently down-regulate HLA class I molecules, malignant leukemic cells carry high levels of HLA class I having a protective effect. 20 NKG2D-L are absent or expressed at low levels in the majority of patients with acute leukemia, 21-23 thereby preventing efficient activating interactions. An additional route of tumor The online version of this article contain...

IntroductionNatural killer (NK) cells are important effectors of the innate immune system involved in the clearance of virus-infected and tumor cells. 1 The activity of NK cells is regulated by receptors with opposing functions, triggering either inhibitory or stimulatory pathways. 2 Killer inhibitory immunoglobulin-like receptors (KIRs) recognize epitopes shared by groups of human leukocyte antigen (HLA) class 1 molecules, and adequate expression of appropriate KIR ligands protects healthy "self" cells against NK cell reactivity. 3 In the absence of this inhibitory pathway, targets become susceptible to NK-mediated lysis. The stimulatory pathway is dependent on engagement of activating receptors, NKG2D, and natural cytotoxicity receptors (NCRs), which transduce signals initiated by the triggering ligands present on infected or transformed cells. 4,5 NKG2D is expressed by NK cells and by T cell receptor (TCR) ␣␤ ϩ CD8 ϩ and TCR ␥␦ ϩ subsets of T cells. 6,7 It recognizes several cell-surface ligands belonging to major histocompatibility complex class I chain-related (MIC) and UL16-binding protein (ULBP) protein families in humans 8,9 and H60 and Rae1 in mice. [10][11][12] MICA and MICB are generally either absent or present at low levels on normal cells, but their expression increases in response to various forms of cellular stress. Up-regulation of MICA and MICB on many human primary tumors of epithelial origin indicates that these ligands mark tumor cells for immune rejection. 13 The ULBP family of NKG2D ligands was identified by the ligands' ability to bind the cytomegalovirus (CMV) glycoprotein UL16. 9,14 Engagement of NKG2D by ULBPs induces NK cell cytotoxicity against tumor targets. 15 The expression patterns of ULBP and MIC molecules in tumor cell lines differ, 9,16 likely reflecting nonredundant functions of these NKG2D ligands.NCRs, which include NKp30, NKp44, and NKp46, are almost exclusively expressed by NK cells. 17 They function as the main activating receptors, and NCR density and NK-mediated cytolytic activity against tumor cells are correlated. 18 In virus-infected cells, viral hemagglutinins are recognized by NKp44 and NKp46. 19,20 However, no endogenous cellular NCR ligands have been identified as yet. Cross-linking of NCRs induces coupling of the signal-transducing adaptor molecules DAP12, CD3, and Fc⑀RI␥, whereas NKG2D in human cells associates with DAP10. 21,22 Use of distinct signaling components allows NKG2D to cooperate with NCRs, in particular on NCR dull NK cells, for recognition and lysis of tumor cells. 23,24 Because the susceptibility of tumors to NK-mediated lysis relies on a balance between inhibitory and triggering signals, through changes in the expression pattern and levels of receptors and their ligands, tumors can evade immune surveillance by NK cells. The online version of this article contains a data supplement.Reprints: Aleksandra Wodnar-Filipowicz, Department of Research, Experimental Hematology, Basel University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland; e-mail...

SummaryWe have previously shown that long-term in vitro proliferating fetal liver pre-B cell lines derived from autoimmune-prone (NZB • NZW)F1 (BW) mice, but not normal (B6 • DBA/ 2)F1 mice, can differentiate in severe combined immunodeficient (SCID) mice to produce elevated levels of serum immunoglobulin (Ig) M and IgG, and high titers ofantinuclear antibodies. The contribution of parental NZB and NZW strains to B cell abnormalities of BW hybrid mice was investigated here by preparing pre-B cells and transferring them into immunodeficient SCID-and RAG-2-targeted mice. We show that transfer of NZB pre-B cells led to a marked lgM hypergammaglobulinemia and to the production of limited amounts of IgG2a. On the other hand, the transfer ofNZW pre-B cell lines led to moderately elevated IgM levels and marked hypergammaglobulinemia of IgG2a. High IgM and low IgG anti-DNA titers are found in the recipients of NZB pre-B cells, whereas those receiving NZW pre-B cells contained lower levels of IgM and high titers of IgG anti-DNA. In marked contrast, essentially identical titers of antibodies directed against a non-self-antigen, DNP, are found in all groups ofpre-B cell recipients. Thus, B-lineage cells of both NZB and NZW parental strains manifest abnormalities associated with the development of this lupus-like disease. Therefore, the present study strongly suggests a complex inheritance of B cell abnormalities in autoimmune-prone (NZB • NZW)FI mice and emphasizes the critical importance of intrinsic B cell defects in the development of routine systemic lupus erythematosus.

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Natural killer (NK) cells are increasingly used in clinical studies in order to treat patients with various malignancies. The following review summarizes platform lectures and 2013–2015 consortium meetings on manufacturing and clinical use of NK cells in Europe and United States. A broad overview of recent pre-clinical and clinical results in NK cell therapies is provided based on unstimulated, cytokine-activated, as well as genetically engineered NK cells using chimeric antigen receptors (CAR). Differences in donor selection, manufacturing and quality control of NK cells for cancer immunotherapies are described and basic recommendations are outlined for harmonization in future NK cell studies.

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