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T Cells and NK Cells1 The Journal of Immunology Silencing Human NKG2D, DAP10, and DAP12 Reduces Cytotoxicity of Activated CD8؉ T Cells and NK Cells1 Mobin Karimi,* Thai M. Cao,* Jeanette A. Baker,* Michael R. Verneris,‡ Luis Soares,†§ and Robert S. Negrin2* Human CD8؉ T cells activated and expanded by TCR cross-linking and high-dose IL-2 acquire potent cytolytic ability against tumors and are a promising approach for immunotherapy of malignant diseases. We have recently reported that in vitro killing by these activated cells, which share phenotypic and functional characteristics with NK cells, is mediated principally by NKG2D. NKG2D is a surface receptor that is expressed by all NK cells and transmits an activating signal via the DAP10 adaptor molecule. Using stable RNA interference induced by lentiviral transduction, we show that NKG2D is required for cytolysis of tumor cells, including autologous tumor cells from patients with ovarian cancer. We also demonstrated that NKG2D is required for in vivo antitumor activity. Furthermore, both activated and expanded CD8؉ T cells and NK cells use DAP10. In addition, direct killing ,was partially dependent on the DAP12 signaling pathway. This requirement by activated and expanded CD8؉ T cells for DAP12 and hence stimulus from a putative DAP12-partnered activating surface receptor, persisted when assayed by anti-NKG2D Ab- mediated redirected cytolysis. These studies demonstrated the importance of NKG2D, DAP10, and DAP12 in human effector cell function. The Journal of Immunology, 2005, 175: 7819–7828. atural killer cells are frontline guardians in surveillance identified, and it is possible that these interactions may yield ad- of pathogens and tumors, and their activation is regu- ditional activating signals (9). CD3␨, FcR␥, and DAP12 intracel- N lated by the integration of excitatory and inhibitory sig- lular ITAM motifs initiate protein tyrosine kinase-dependent sig- nals initiated by membrane-bound receptor molecules (1, 2). In- naling pathways (10), whereas DAP10 contains a YxxM activation hibitory signals are mediated by monomeric receptors possessing motif that triggers the lipid kinase cascade (11–13). intracytoplasmic immunoreceptor tyrosine-based inhibition motifs In human NK cells, DAP10 is the exclusive binding partner and that recruit tyrosine protein phosphatases (3). Activating signals signaling intermediate for NKG2D (14). NKG2D is a potent acti- are generated from more diverse and complementary groups of vating receptor whose ligands include proteins induced by cellular membrane molecules that, upon ligand binding, can oligomerize stress and malignant transformation, such as MHC class I-related with different cytoplasmic adaptor polypeptides to form distinct by guest on October 1, 2021. Copyright 2005 Pageant Media Ltd. protein (MICA) and -B and members of the UL16-binding pro- signaling complexes. In human NK cells, these types of activating teins, and is thought to have a particularly important role in anti- receptors include NKG2D, which associate with the adaptor mol- tumor immunity (15). ecule disulphide adaptor molecule (DAP)3-10, and the low-affinity The expression and function of these activating signaling com- IgG FcR CD16, which noncovalently couples with the adaptor plexes are not limited to NK cells. DAP12 is expressed in granu- molecules CD3␨ and FcR␥. CD3␨, FcR␥, and another adaptor mol- locytes, monocytes, as well as CD4ϩ T cells, and DAP12-deficient ecule found in NK cells, named DAP12 (4, 5), have in common a mice have been shown to have defects in dendritic cells and NK membrane-bound structure with a cytoplasmic domain bearing one cells (16–19). NKG2D has been identified on ␥␦ TCRϩ T cells or more ITAM motifs. Human DAP12 is known to mediate acti- and human CD8ϩ T cells, where it appears to have costimulatory ϩ http://classic.jimmunol.org vating signals from diverse binding partners that include killer cell activity and can be induced on activated mouse CD8 T cells Ig-like receptors S such as killer cell Ig-like receptor 2DS2, the (20–22). We have recently reported that NKG2D expression is activation-induced NKp44 receptor, and HLA-E binding CD94/ up-regulated by human CD8ϩ T cells activated and expanded ex NKG2C heterodimers (5–8). DAP12 has been shown to associate vivo in the presence of IFN-␥, high-dose IL-2, and TCR cross- with a host of other NK cell surface proteins that have yet to be linking with an anti-CD3 mAb (23). Activated and expanded T cells up-regulate cytotoxic effector molecules, acquire functional Downloaded from and phenotypic properties that resemble NK cells, and develop *Division of Blood and Marrow Transplantation and †Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, broad cytotoxicity against a variety of malignant cell targets, in- Stanford, CA 94305; ‡Division of Pediatric Blood and Marrow Diseases, Department cluding autologous leukemic blasts (24–28). This acquisition of of Pediatrics, University of Minnesota, Minneapolis, MN 55455; and §Institute of Biomedical Pharmacology, Curitiba, Brazil cytotoxicity, which is MHC unrestricted, coincides with the induc- tion of DAP10 expression, and the majority of killing ability is Received for publication May 18, 2005. Accepted for publication September 21, 2005. accounted for by NKG2D signaling. ϩ The costs of publication of this article were defrayed in part by the payment of page Activated and expanded CD8 T cells may have considerable charges. This article must therefore be hereby marked advertisement in accordance therapeutic utility as an immune-based strategy aimed at eradica- with 18 U.S.C. Section 1734 solely to indicate this fact. tion or suppression of malignant diseases. These T cells have broad 1 This work was supported in part by Grants KO8HL04505, P01CA049605, and in vitro and in vivo biological activity against inoculated tumors R01CA080006 from the National Institutes of Health. after both syngeneic and allogeneic bone marrow transplantation 2 Address correspondence and reprint requests to Dr. Robert S. Negrin, Division of Blood and Marrow Transplantation, Stanford University, CCSR Room 2205, 269 in rodent models (29, 30). Autologous infusion of cells of this type West Campus Drive, Stanford, CA 94305-5170. E-mail: [email protected] in patients has been associated with minimal toxicity, can reduce Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 7820 NKG2D, DAP10, AND DAP12 IN CD8ϩ T AND NK CELL CYTOTOXICITY the risk of tumor recurrence in patients with hepatocellular carci- NKG2D, DAP10, and DAP12 RNAi noma after surgical resection, and may induce partial remissions in Nucleotide sequences for short hairpin RNA (shRNA) are summarized in patients with relapse of lymphoma after bone marrow transplan- Table I. A previously reported RNAi sequence specific for murine CD8␣ tation (31, 32). In this study, we extended our evaluation of the (mCD8) was used as a nonspecific control (33). Oligonucleotides were signaling requirements for induction of cytotoxicity by activated designed that incorporated these sequences within a short hairpin structure, Ј Ј and expanded human CD8ϩ T cells. We used a combination of in using the stem loop sequence 5 -TCAAGAGA-3 , which were then cloned between MluI and ClaI sites downstream of an H1 promoter in the plasmid vitro and in vivo assays against tumor cell lines and autologous pLVTHM as previously described (34). Plasmid pLVTHM, derived from tumor targets and gene targeting by RNA interference (RNAi). We pSUPERn which contains a GFP expression cassette upstream of the H1 show that both DAP10 and DAP12, in addition to NKG2D, con- promoter (35), was a gift from D. Trono (University of Geneva, Geneva, tribute major activating signals in regulating the cytotoxicity of Switzerland). For some experiments we replaced the GFP gene on ϩ pLVTHM with a DsRed reporter gene via PmeI and SpeI linkers. 293 cells activated and expanded human CD8 T cells. We show, further- were transfected using the calcium phosphate method with 10 ␮g pLVThM more, that each of these molecules, including DAP12, has a non- lentivirus, 3.5 ␮g of vesicular stomatitis virus G plasmid, and 6.5 ␮gof redundant and partially obligate signaling role in triggering tumor CMV⌬R8.74 according to standard protocols (36). After 16 h, the medium killing. was changed, and recombinant lentivirus vectors were harvested 24–48 h later. CD8ϩ T cell or NK cell infection was performed three times at 24-h intervals. For each infection, cells were plated in 48-well plates at 1 ϫ 105 Materials and Methods cells/well and infected in the presence of protamine and hexadimethrin. Spin infection was performed at 1200 rpm for 90 min at 37°C. Four days mAb reagents and flow cytometry after the first infection, transduced cells were isolated by FACS sorting for ϩ Ͼ The mAbs used in this study were the following: CD3 (UCHT1), CD8 GFP cells to 99% purity. (RPA-T8), CD16 (3G8), CD56 (NCAM16-2), and isotype control (IgG) were purchased from BD Biosciences as either FITC or PE conjugates. Cell lines and autologous tumor cell isolation Purified NKG2D were purchased from R&D Systems, and PE NKG2D-PE RPMI 1640, a human myeloma cell line cultured in cRPMI, and P815, a and NKG2D-allophycoyanin were purchased from Beckman Coulter. La- murine mastocytoma cell line cultured in complete DMEM, were both beled cells were analyzed on either a FACScan or an LSR-II instrument purchased from American Type Culture Collection. UCI101 (a gift from (BD Biosciences) maintained by the Stanford Shared FACS Facility (Stan- S. Y. Liao, University of California, Irvine, CA) is a human ovarian car- ford University). For micromagnetic cell separation, human CD8 (BW135/ cinoma cell line cultured in complete IDMEM. Luciferase expressing 80) MicroBeads, human CD16 MicroBeads (130-045-701), or human HEA UCI101 (UCI101-luc) was generated according to a modified protocol that MicroBeads (130-061-101) were used for positive selection using an Au- we have previously described (37).
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