Natural killer cells j zimmer (springer, 2010)

Natural Killer Cells Jacques Zimmer Editor Natural Killer Cells At the Forefront of Modern Immunology Editor Dr Jacques Zimmer Centre de Recherche Public de la Sante´ Lab Immuno-Allergologie 84 Val Fleuri 1526 Luxembourg Luxembourg jacques.zimmer@crp-sante.lu ISBN 978-3-642-02308-8 e-ISBN 978-3-642-02309-5 DOI 10.1007/978-3-642-02309-5 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009930465 # Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer Violations are liable to prosecution under the German Copyright Law The use of general descriptive names, registered names, trademarks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use Cover design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface It is an interesting and even exciting experience to be the editor of a scientific book After the decision of producing the book has been made together with the publisher, the first step is to establish the list of topics to be covered and the list of potential authors Regarding the latter, the editor is in the same situation as the director of a movie in that he wants to have as much stars in the field as possible to contribute a chapter For that, the potential authors have to be contacted and invited They can be subdivided into three groups: (1) those who reply and accept to write a chapter, (2) those who reply but not accept to write a chapter, and finally (3) those who not even reply In my case, I was lucky that the vast majority of authors I contacted with my request were in group 1, and so I did not face too many difficulties in filling the table of contents However, there was a small subgroup containing one author who first submitted his chapter but subsequently decided to publish it in another book In group 2, people claimed that they were too busy, which is a valuable argument In any case, I am very grateful to all the authors who contributed for the time and energy they spent in doing so Why publish a book about NK cells in 2009? Simply because they are still, nearly two decades after becoming fashionable, at the forefront of modern immunology Nearly every month, new and exciting findings about NK cells are published, and they have not yet revealed all their secrets They are by far not only of academic interest, as it becomes increasingly clear that they can be exploited in the therapy of human diseases, in particular in the fight against cancer and infections This book covers the state of the art of most aspects of NK cell biology, including most recent topics like NK cell development and education, NK cell trogocytosis, NK cells and allergy, regulatory NK cells and interactions between NK cells and regulatory T cells, another type of immunological forefront actors I am confident that the book will be useful to everyone who is interested in those fascinating NK cells April 2009 Jacques Zimmer v Contents Natural Killer Cells: Deciphering Their Role, Diversity and Functions Vicente P.C Peixoto deToledo, Renato Sathler-Avelar, Danielle Marquete Vitelli-Avelar, Vanessa Peruhype-Magalha˜es, Denise Silveira-Lemos, Ana Carolina Campi-Azevedo, Marile´ia Chaves Andrade, Andre´a Teixeira-Carvalho, and Olindo Assis Martins-Filho Dissecting Human NK Cell Development and Differentiation 39 Nicholas D Huntington, Jean-Jacques Mention, Christian Vosshenrich, Naoko Satoh-Takayama, and James P Di Santo Diversity of KIR Genes, Alleles and Haplotypes 63 D Middleton, F Gonzalez-Galarza, A Meenagh, and P.A Gourraud NK Cell Education and CIS Interaction Between Inhibitory NK Cell Receptors and Their Ligands 93 Jacques Zimmer, Franc¸ois Hentges, Emmanuel Andre`s, and Anick Chalifour Trogocytosis and NK Cells in Mouse and Man 109 Kiave-Yune HoWangYin, Edgardo D Carosella, and Joel LeMaoult Virus Interactions with NK Cell Receptors 125 Vanda Juranic´ Lisnic´, Iva Gasparovic´, Astrid Krmpotic´, and Stipan Jonjic´ The Role of NK Cells in Bacterial Infections 153 Brian P McSharry, and Clair M Gardiner vii viii Contents NK Cells and Autoimmunity 177 Hanna Brauner, and Petter Hoăglund NK Cells and Allergy 191 Tatiana Michel, Maud The´re´sine, Aure´lie Poli, Franc¸ois Hentges, and Jacques Zimmer Natural Killer Cells and Their Role in Hematopoietic Stem Cell Transplantation 199 Deborah L.S Goetz, and William J Murphy NK Cells, NKT Cells, and KIR in Solid Organ Transplantation 221 Cam-Tien Le and Katja Kotsch NK Cells in Autoimmune and Inflammatory Diseases 241 Nicolas Schleinitz, Nassim Dali-Youcef, Jean-Robert Harle, Jacques Zimmer, and Emmanuel Andres Natural Killer Cells and the Skin 255 Dagmar von Bubnoff NK Cells in Oncology 267 Sigrid De Wilde, and Guy Berchem The Role of KIR in Disease 275 Salim I Khakoo Interactions Between NK Cells and Dendritic Cells 299 Guido Ferlazzo Modulation of T Cell-Mediated Immune Responses by Natural Killer Cells 315 Alessandra Zingoni, Cristina Cerboni, Michele Ardolino, and Angela Santoni Interactions Between NK Cells and Regulatory T Cells 329 Magali Terme, Nathalie Chaput, and Laurence Zitvogel Interactions Between B Lymphocytes and NK Cells: An Update 345 Dorothy Yuan, Ning Gao, and Paula Jennings The Regulatory Natural Killer Cells 369 Zhigang Tian and Cai Zhang Contents ix NK Cells and Microarrays 391 Esther Wilk and Roland Jacobs Natural Killer Cells in the Treatment of Human Cancer 405 Karl-Johan Malmberg and Hans-Gustaf Ljunggren Index 423 Natural Killer Cells: Deciphering Their Role, Diversity and Functions Vicente P.C Peixoto deToledo, Renato Sathler-Avelar, Danielle Marquete Vitelli-Avelar, Vanessa Peruhype-Magalha˜es, Denise Silveira-Lemos, Ana Carolina Campi-Azevedo, Marile´ia Chaves Andrade, Andre´a TeixeiraCarvalho, and Olindo Assis Martins-Filho Abstract Natural killer (NK) cells represent the third largest lymphoid cell population in mammals and are critical in innate immune responses These cells express a large repertoire of receptors, named inhibitors and activators that mediate their function NK cells occur naturally, not require previous sensitization to engage their activity and are distributed to blood, as circulating cells, and to other organs of the body as resident cells No longer considered simple “killing machines,” NK cells have gained recognition for their abilities to secrete cytokines/chemokines that influence the differentiation of the adaptive immune responses, control viral/parasitic infections and participate in pathological and physiological mechanisms such as transplant rejection and the vascularization of implanting embryos during pregnancy Here, we describe in detail the ontogeny of NK cells, their role in innate immunity from the point of view of their phenotypic features and functional activities as well as their function in health and disease We also discuss the role of NK cells in immunological events in murine models This review aims to highlight what is currently known and what remains to be understood about these essential innate immune cells V.P.C Peixoto de Toledo (*) Departamento de Ana´lises Clı´nicas e Toxicolo´gicas, Faculdade de Farma´cia, Universidade Federal de Minas Gerais, Avenida Antoˆnio Carlos, 6627 Belo Horizonte, MG, Brasil, 31270-901 e-mail: vtoledo@ufmg.br R Sathler-Avelar, D Marquete Vitelli-Avelar, V Peruhype-Magalha˜es, D Silveira-Lemos, A Carolina Campi-Azevedo, M Chavs Andrade, A Teixeira-Carvalho and O Assis Martins-Filho Laborato´rio de Biomarcadores de Diagno´stico e Monitorac¸a˜o, Centro de Pesquisas Rene´ Rachou, Fundac¸a˜o Oswaldo Cruz, Av Augusto de Lima, 1715 Barro Preto, Belo Horizonte, MG, Brasil, 30190-002 V Peruhype-Magalha˜es Laborato´rio de Pesquisas Clı´nicas, Centro de Pesquisas Rene´ Rachou, Fundac¸a˜o Oswaldo Cruz, Av Augusto de Lima, 1715 Barro Preto, Belo Horizonte, MG, Brasil, 30190-002 D Silveira-Lemos Laborato´rio de Imunopatologia, NUPEB, Departamento de Ana´lises Clı´nicas, Escola de Farma´cia, Universidade Federal de Ouro Preto, Rua Costa Sena s/n, Ouro Preto, MG, Brasil, 35400-000 J Zimmer (ed.), Natural Killer Cells, DOI 10.1007/978-3-642-02309-5_1, # Springer-Verlag Berlin Heidelberg 2010 V.P.C.P de Toledo et al Introduction Natural killer (NK) cells represent the third largest lymphoid cell population in mammals and are critical in innate immune responses [1] They are characterized by the expression of a varied repertoire of receptors, named inhibitors and activators, that mediate their function [2] These cells are large, granular, bone-marrow- as well as lymph node-derived lymphocytes However, NK cells are distinct from T cells or B cells and have distinct morphologic, phenotypic and functional properties These cells occur naturally and unlike T cells or B cells, not require sensitization for the expression of their activity [3] NK cells are distributed to blood as circulating cells and to other organs of the body as resident cells In peripheral blood, they are characteristically described as having the morphology of large granular lymphocytes (LGL) [4], whereas in tissues, the microenvironment of the organ has influence on phenotype and activity of NK cells as demonstrated in lung and spleen [5] NK cell functions can be classified in three categories: (A) Cytotoxicity – NK cells can kill certain virally infected cells and tumor target cells regardless of their MHC expression [6] NK cells possess relatively large numbers of cytolytic granules, which are secretory lysosomes containing perforin and various granzymes Upon contact between an NK cell and its target, these granules travel to the contact zone with the susceptible target cell (the so-called immunological synapse), and the contents are extruded to effect lysis Perforin-dependent cytotoxicity is the major mechanism of NK cell lysis, although NK cells can also kill in a perforin-independent manner utilizing FAS ligand, TNF or TNF-related apoptosis-inducing ligand (TRAIL), albeit less efficiently and in a slower time kinetic; (B) Cytokine and chemokine secretion – NK cells are best noted for their ability to produce IFN-g but also produce a number of other cytokines and chemokines including TNF-a, GMCSF, interleukin(IL)-5, IL-13, CCL3/MIP-1a, CCL4/MIP-1b and CCL5/RANTES [7–9] Killing and cytokine secretion are probably mediated by two different subsets of human NK cells characterized by the intensity of expression of CD56 on their surface; and (C) Contact-dependent cell costimulation: NK cells express several costimulatory ligands including CD40L (CD154) and OX40L, which allow them to provide a costimulatory signal to T cells or B cells [10, 11] Thus, NK cells may serve as a bridge in an interactive loop between innate and adaptive immunity Dendritic cells (DC) stimulate NK cells, which then deliver a costimulatory signal to T or B cells allowing for an optimal immune response The current model for NK cell activation and inhibition is one based upon the balance of function between specific activating and inhibitory receptors If the balance favors inhibitory signaling, then intracellular events leading to cell function will not progress If the balance favors activation signals, NK cells can then progress through a series of intracellular stages and checkpoints to exert their function The balance of inhibitory and stimulatory signals received by a NK cell determines the outcome of interactions with target cells Normal target cells are protected from killing by NK cells when signals delivered by stimulatory ligands are balanced by inhibitory signals delivered by self MHC class I molecules Natural Killer Cells in the Treatment of Human Cancer 413 advanced solid tumors [107, 108] Expansion protocols provide greater numbers of NK cells to be used for adoptive therapy that might be desired in some situations For such expansions to be effective, it is important that the expansion of NK cells ex vivo is not associated with phenotypic changes, linage deviation, and/or selective expansion of specific subsets, such that their antitumor function will be affected Another aspect to consider, apart from consequences of activation and proliferation, is that in vitro manipulation does not alter the NK cells’ ability to mediate cell–cell interactions, trafficking, and homing to desired location With respect to autologous NK cells, one may predict that they may be more effective in situations where tumors express low levels of MHC class I molecules 12 Future Possibilities and Strategies for Adoptive NK Cell Immunotherapy We have recently described critical questions that must be considered for the development of successful NK cell-based adoptive immunotherapy [22] Below, we briefly discuss some issues with respect to the possible advantages, but also difficulties, of using allogeneic NK cells in future settings of adoptive NK cellbased immunotherapy As autologous NK cells are inhibited by self-MHC class I molecules, allogeneic NK cells may, in certain situations, represent a better cellular population for adoptive immunotherapy in vivo The latter choice applies particularly to situations in which tumor targets express normal levels of MHC class I molecules in combination with low or only moderate expression of ligands for activating receptors NK cell alloreactivity depends on “missing” KIR ligands (MHC class I) in the recipient However, although NK cell alloreactivity is predicted by genetic algorithms based on KIR- and HLA-genotyping, the numbers of alloreactive NK cells in a given donor vary significantly, from 0% to 62% of the NK cells [114] Predicting the effectiveness of therapy may thus be on the basis of assessment of the NK cell repertoire and selection of a donor with the largest alloreactive NK cell subset A prerequisite for survival of the infused cells is that they are not rejected by the recipient’s immune system If donor derived NK cells are infused at the time of transplantation they may engraft along with the stem cells because of the pretransplant conditioning However, rejection of allogeneic NK cells represents a major challenge for specific NK cell therapy in the absence of myeloablative conditioning It is likely that some type of conditioning will be required for effective transfer of allogeneic NK cells Apart from preventing rejection, such regimens may also eradicate regulatory T cells that could otherwise interfere with the proliferation and function of the donor derived NK cells [115] Moreover, there is reduced competition for growth factors during the homeostatic proliferation that follows lymphodepletion and the surge of cytokines, including IL-15, may promote proliferation, in vivo survival, and expansion of the infused NK cells Indeed, in the studies by Miller and collaborators [23], NK cell expansion was dependent on an intense 414 K.-J Malmberg and H.-G Ljunggren preparative regimen (high-dose cyclophosphamide/fludarabin) The latter regimen is similar to that used recently by Rosenberg and colleagues to induce homeostatic proliferation of adoptively transferred T cells [116] As understanding of the conditions required for engraftment of NK cells improves, dosing of the preparative regimen will be more precise and the risks associated with high-dose myeloablative treatments will decrease 13 Combination Therapies may Develop into Promising Treatment Options for Some Cancers Finally, we predict that combination therapies including NK cells (directly or indirectly) will become ever more important in the future Ligands for the activating receptor NKG2D are upregulated by genotoxic stress and stalled DNA replication, through activation of major DNA damage checkpoint pathways initiated by ATM or ATR protein kinases [117, 118] Thus, the response to DNA damage alerts the immune system to the presence of potentially dangerous cells As several of the currently used chemotherapeutic drugs, as well as ionizing irradiation, act via the DNA damage response pathway, a mild preconditioning using these drugs and/or local ionizing irradiation might sensitize tumor cells to immune recognition, leading to synergistic antitumor effects Similarly, new generation cancer drugs such as the proteasome inhibitors and the histone deacetylase inhibitors can upregulate the death receptor DR5, sensitizing tumor cells to TRAIL-mediated killing by NK cells [119–121] Histone deacetylase inhibitors induce MICA/B expression [122] Imatinib mesylate, previously discussed as a potential stimulator of innate immunity to tumors, was also shown to influence the expression and shedding of the activating NK cell ligand MICA on Bcr/Abl positive targets [123] Thus, although NKG2D expression on NK cells is restored upon Imatinib treatment, this may lead to decreased tumor targeting because of reduced MICA expression [123, 124] As has been discussed, NK cells are major effectors in mediating ADCC Rituximab (Mabthera), a chimeric mouse/human antibody that recognizes the CD20 antigen expressed on mature B lymphocytes [125], is currently given alone or combined with chemotherapy to patients with non-Hodgkin’s lymphomas One mechanism of this antibody’s action is the induction of ADCC mediated by NK cells [126, 127] Trials combining Rituximab with IL-2 to activate and expand the pool of NK cells available for ADCC are under way [128] Several other antibodies are being evaluated in clinical practices and for many of them such as, e.g., Herceptin, at least part of their effector mechanism seems to be mediated by NK cells via ADCC [129, 130] These and other findings suggest the possibility of using antibodies in conjunction with adoptive NK cell immunotherapy or NK cell stimulation-based protocols A related therapeutic approach is the use of bispecific antibodies to promote NK cell targeting of tumors Experimental and clinical data suggest that bispecific antibodies can be beneficial in tumor treatment One approach is the use of antibodies specific for CD16 on NK cells and CD19 on B cell Natural Killer Cells in the Treatment of Human Cancer 415 lymphomas or HER2/neu on breast cancers to target tumors expressing these, respective antigens [131] Interestingly, clinical responses have been observed in patients with Hodgkin’s lymphoma treated with bispecific antibodies against CD16 and CD30 [132] 14 Human Cancers that may be Subject to NK Cell Targeting It is already evident from studies performed in vitro and even in some clinical studies that certain tumor types may be better suited than others for NK cell-based immunotherapy The presence on human tumors of ligands for activating receptors provides an important prerequisite for NK cell activation, and thus for the potential of achieving good clinical results [51] An illustration of this is the inefficient NK cell killing of lymphoid compared to myeloid leukemias that may be caused, at least in part, by the absence of LFA-1 ligand expression [95] Likewise, low expression of MHC class I molecules, particularly in situations where KIR–ligand mismatching (“missing-self”-reactivity) does not prevail, is also important Most immunotherapy trials have been performed in patients with significant tumor burdens, where conventional therapies were ineffective The best clinical setting for most cellular therapies including NK cell-based immunotherapy is probably when the tumor burden is small, i.e., in minimal residual disease [133] NK cell therapy against large solid tumors presents special problems including not only the size of the tumor per se but also the presumed necessity of NK cells to infiltrate the tumor Despite the knowledge gained so far about the mechanisms that control trafficking of NK cells, we still know too little about the requirements for NK cell homing to and infiltration of tumors It is known, however, that chemokines are required to attract NK cells to tumor sites NK cells express a wide array of chemokine receptors on their cell surface Different NK cell subsets can be identified on the basis of chemokine receptor expression and the pattern of expression is likely highly dependent upon the activation status of the NK cells [8] 15 Conclusion As outlined above, we envisage many ways in which NK cells can be stimulated, manipulated, and used in settings of human cancer therapy Strategies will not only be straight forward, and therapeutic results will not always be observed Yet, we see a potential in the possibilities discussed In particular, combination therapies involving NK cells, either directly or indirectly, may pave the way for new treatment strategies Acknowledgments We are supported by the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Cancer Society, the Royal Swedish Academy of Sciences, 416 K.-J Malmberg and H.-G Ljunggren the Swedish Children’s Cancer Society, the Cancer Society of Stockholm, the Karolinska Institutet, and the Karolinska University Hospital This content of chapter is, in part, on the basis of a symposium paper published in Cancer Immunology Immunotherapy, Springer-Verlag, 2008 (Oct;57(10):1541-52 Epub 2008 Mar 4) References Kiessling R, Klein E, Wigzell H (1975) "Natural" killer cells in the mouse I Cytotoxic cells with specificity for mouse Moloney leukemia cells Specificity and distribution according to genotype Eur J Immunol 5:112 Huntington ND, Vosshenrich CA, Di Santo JP (2007) Developmental pathways that generate natural-killer-cell diversity in mice and humans Nat Rev Immunol 7:703 Lanier LL (2005) NK cell recognition Annu Rev Immunol 23:225 Moretta A, Bottino C, Mingari MC et al (2002) What is a natural killer cell? Nat Immunol 3:6 Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors EMBO J 23:255 Bryceson YT, March ME, Ljunggren HG et al (2006) Activation, coactivation, and costimulation of resting human natural killer cells Immunol Rev 214:73 Moretta A, Marcenaro E, Sivori S et al (2005) Early liaisons between cells of the innate immune system in inflamed peripheral tissues Trends Immunol 26:668 Robertson MJ (2002) Role of chemokines in the biology of natural killer cells J Leukoc Biol 71:173 Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets Trends Immunol 22:633 10 Farag SS, Fehniger TA, Ruggeri L et al (2002) Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect Blood 100:1935 11 Di Santo JP (2006) Natural killer cell developmental pathways: a question of balance Annu Rev Immunol 24:257 12 Farag SS, Caligiuri MA (2006) Human natural killer cell development and biology Blood Rev 20:123 13 Smyth MJ, Hayakawa Y, Takeda K et al (2002) New aspects of natural-killer-cell surveillance and therapy of cancer Nat Rev Cancer 2:850 14 Wu J, Lanier LL (2003) Natural killer cells and cancer Adv Cancer Res 90:127 15 Algarra I, Ohlen C, Perez M et al (1989) NK sensitivity and lung clearance of MHC-classI-deficient cells within a heterogeneous fibrosarcoma Int J Cancer 44:675 16 Ljunggren HG, Karre K (1985) Host resistance directed selectively against H-2-deficient lymphoma variants Analysis of the mechanism J Exp Med 162:1745 17 Street SE, Hayakawa Y, Zhan Y et al (2004) Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells J Exp Med 199:879 18 Guimaraes F, Guven H, Donati D et al (2006) Evaluation of ex vivo expanded human NK cells on antileukemia activity in SCID-beige mice Leukemia 20:833 19 Carlsten M, Bjorkstrom NK, Norell H et al (2007) DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells Cancer Res 67:1317 20 Castriconi R, Dondero A, Corrias MV et al (2004) Natural killer cell-mediated killing of freshly isolated neuroblastoma cells: critical role of DNAX accessory molecule-1-poliovirus receptor interaction Cancer Res 64:9180 21 El-Sherbiny YM, Meade JL, Holmes TD et al (2007) The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells Cancer Res 67:8444 Natural Killer Cells in the Treatment of Human Cancer 417 22 Ljunggren HG, Malmberg KJ (2007) Prospects for the use of NK cells in immunotherapy of human cancer Nat Rev Immunol 7:329 23 Miller JS, Soignier Y, Panoskaltsis-Mortari A et al (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer Blood 105:3051 24 Ruggeri L, Aversa F, Martelli MF et al (2006) Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self Immunol Rev 214:202 25 Ruggeri L, Capanni M, Urbani E et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants Science 295:2097 26 Hayakawa Y, Smyth MJ (2006) Innate immune recognition and suppression of tumors Adv Cancer Res 95:293 27 Malmberg KJ (2004) Effective immunotherapy against cancer: a question of overcoming immune suppression and immune escape? Cancer Immunol Immunother 53:879 28 Malmberg KJ, Ljunggren HG (2006) Escape from immune- and nonimmune-mediated tumor surveillance Semin Cancer Biol 16:16 29 Costello RT, Sivori S, Marcenaro E et al (2002) Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia Blood 99:3661 30 Jager MJ, Hurks HM, Levitskaya J et al (2002) HLA expression in uveal melanoma: there is no rule without some exception Hum Immunol 63:444 31 Salih HR, Rammensee HG, Steinle A (2002) Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding J Immunol 169:4098 32 Castriconi R, Cantoni C, Della Chiesa M et al (2003) Transforming growth factor beta inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells Proc Natl Acad Sci U S A 100:4120 33 Ghiringhelli F, Menard C, Terme M et al (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner J Exp Med 202:1075 34 Smyth MJ, Teng MW, Swann J et al (2006) CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer J Immunol 176:1582 35 Glas R, Sturmhofel K, Hammerling GJ et al (1992) Restoration of a tumorigenic phenotype by beta 2-microglobulin transfection to EL-4 mutant cells J Exp Med 175:843 36 Hoglund P, Ljunggren HG, Ohlen C et al (1988) Natural resistance against lymphoma grafts conveyed by H-2Dd transgene to C57BL mice J Exp Med 168:1469 37 Karre K, Ljunggren HG, Piontek G et al (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy Nature 319:675 38 Ljunggren HG, Karre K (1990) In search of the missing self: MHC molecules and NK cell recognition Immunol Today 11:237 39 Karlhofer FM, Ribaudo RK, Yokoyama WM (1992) MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells Nature 358:66 40 Moretta A, Vitale M, Bottino C et al (1993) P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities J Exp Med 178:597 41 Moretta L, Bottino C, Pende D et al (2004) Different checkpoints in human NK-cell activation Trends Immunol 25:670 42 Zamai L, Ponti C, Mirandola P et al (2007) NK cells and cancer J Immunol 178:4011 43 Pessino A, Sivori S, Bottino C et al (1998) Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity J Exp Med 188:953 44 Vitale M, Bottino C, Sivori S et al (1998) NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis J Exp Med 187:2065 45 Bottino C, Castriconi R, Moretta L et al (2005) Cellular ligands of activating NK receptors Trends Immunol 26:221 418 K.-J Malmberg and H.-G Ljunggren 46 Pogge von Strandmann E, Simhadri VR, von Tresckow B et al (2007) Human Leukocyte Antigen-B-Associated Transcript Is Released from Tumor Cells and Engages the NKp30 Receptor on Natural Killer Cells Immunity 27:965 47 Bauer S, Groh V, Wu J et al (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA Science 285:727 48 Bottino C, Castriconi R, Pende D et al (2003) Identification of PVR (CD155) and Nectin2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule J Exp Med 198:557 49 Chang CC, Ferrone S (2006) NK cell activating ligands on human malignant cells: molecular and functional defects and potential clinical relevance Semin Cancer Biol 16:383 50 Costello RT, Fauriat C, Sivori S et al (2004) NK cells: innate immunity against hematological malignancies? Trends Immunol 25:328 51 Moretta L, Bottino C, Pende D et al (2006) Surface NK receptors and their ligands on tumor cells Semin Immunol 18:151 52 Mendez R, Ruiz-Cabello F, Rodriguez T et al (2007) Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy Cancer Immunol Immunother 56:88 53 Moretta L, Moretta A (2004) Killer immunoglobulin-like receptors Curr Opin Immunol 16:626 54 Parham P (2005) MHC class I molecules and KIRs in human history, health and survival Nat Rev Immunol 5:201 55 Wagtmann N, Biassoni R, Cantoni C et al (1995) Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra- and intracellular domains Immunity 2:439 56 Braud VM, Allan DS, O’Callaghan CA et al (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C Nature 391:795 57 Bryceson YT, March ME, Ljunggren HG et al (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion Blood 107:159 58 Cerwenka A, Baron JL, Lanier LL (2001) Ectopic expression of retinoic acid early inducible1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo Proc Natl Acad Sci U S A 98:11521 59 Diefenbach A, Jensen ER, Jamieson AM et al (2001) Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity Nature 413:165 60 Wallace ME, Smyth MJ (2005) The role of natural killer cells in tumor control–effectors and regulators of adaptive immunity Springer Semin Immunopathol 27:49 61 Smyth MJ, Cretney E, Kelly JM et al (2005) Activation of NK cell cytotoxicity Mol Immunol 42:501 62 Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway Nat Rev Immunol 2:735 63 Screpanti V, Wallin RP, Grandien A et al (2005) Impact of FASL-induced apoptosis in the elimination of tumor cells by NK cells Mol Immunol 42:495 64 Smyth MJ, Crowe NY, Pellicci DG et al (2002) Sequential production of interferon-gamma by NK1.1(+) T cells and natural killer cells is essential for the antimetastatic effect of alphagalactosylceramide Blood 99:1259 65 Becknell B, Caligiuri MA (2005) Interleukin-2, interleukin-15, and their roles in human natural killer cells Adv Immunol 86:209 66 Colucci F, Caligiuri MA, Di Santo JP (2003) What does it take to make a natural killer? Nat Rev Immunol 3:413 67 Bryceson YT, Rudd E, Zheng C et al (2007) Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis (FHL4) patients Blood 110:1906 68 Mrozek E, Anderson P, Caligiuri MA (1996) Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells Blood 87:2632 Natural Killer Cells in the Treatment of Human Cancer 419 69 Waldmann TA, Dubois S, Tagaya Y (2001) Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy Immunity 14:105 70 Rodella L, Zamai L, Rezzani R et al (2001) Interleukin and interleukin 15 differentially predispose natural killer cells to apoptosis mediated by endothelial and tumour cells Br J Haematol 115:442 71 Lauwerys BR, Garot N, Renauld JC et al (2000) Cytokine production and killer activity of NK/T-NK cells derived with IL-2, IL-15, or the combination of IL-12 and IL-18 J Immunol 165:1847 72 Brady J, Hayakawa Y, Smyth MJ et al (2004) IL-21 induces the functional maturation of murine NK cells J Immunol 172:2048 73 Parrish-Novak J, Dillon SR, Nelson A et al (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function Nature 408:57 74 Farag SS, Caligiuri MA (2004) Cytokine modulation of the innate immune system in the treatment of leukemia and lymphoma Adv Pharmacol 51:295 75 Smyth MJ, Cretney E, Kershaw MH et al (2004) Cytokines in cancer immunity and immunotherapy Immunol Rev 202:275 76 Rosenberg SA (2000) Interleukin-2 and the development of immunotherapy for the treatment of patients with cancer Cancer J Sci Am 6(Suppl 1):S2 77 Fehniger TA, Cooper MA, Caligiuri MA (2002) Interleukin-2 and interleukin-15: immunotherapy for cancer Cytokine Growth Factor Rev 13:169 78 Roda JM, Joshi T, Butchar JP et al (2007) The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines Clin Cancer Res 13:6419 79 Gosselin J, TomoIu A, Gallo RC et al (1999) Interleukin-15 as an activator of natural killer cell-mediated antiviral response Blood 94:4210 80 Ozdemir O, Ravindranath, Y, Savasan S (2005) Mechanisms of superior anti-tumor cytotoxic response of interleukin 15-induced lymphokine-activated killer cells J Immunother 28:44 81 Waldmann TA (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design Nat Rev Immunol 6:595 82 Kobayashi H, Dubois S, Sato N et al (2005) Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance Blood 105:721 83 Hayashi T, Hideshima T, Akiyama M et al (2005) Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application Br J Haematol 128:192 84 Fujii H, Trudeau JD, Teachey DT et al (2007) In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides Blood 109:2008 85 Borg C, Terme M, Taieb J et al (2004) Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects J Clin Invest 114:379 86 Smyth MJ (2006) Imatinib mesylate–uncovering a fast track to adaptive immunity N Engl J Med 354:2282 87 Ullrich E, Bonmort M, Mignot G et al (2007) Therapy-induced tumor immunosurveillance involves IFN-producing killer dendritic cells Cancer Res 67:851 88 Brandau S, Riemensberger J, Jacobsen M et al (2001) NK cells are essential for effective BCG immunotherapy Int J Cancer 92:697 89 Sheridan C (2006) First-in-class cancer therapeutic to stimulate natural killer cells Nat Biotechnol 24:597 90 Koh CY, Blazar BR, George T et al (2001) Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo Blood 97:3132 91 Koh CY, Ortaldo JR, Blazar BR et al (2003) NK-cell purging of leukemia: superior antitumor effects of NK cells H2 allogeneic to the tumor and augmentation with inhibitory receptor blockade Blood 102:4067 92 Sentman CL, Barber MA, Barber A et al (2006) NK cell receptors as tools in cancer immunotherapy Adv Cancer Res 95:249 420 K.-J Malmberg and H.-G Ljunggren 93 Imai C, Iwamoto S, Campana D (2005) Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells Blood 106:376 94 Uherek C, Tonn T, Uherek B et al (2002) Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction Blood 100:1265 95 Ruggeri L, Capanni M, Casucci M et al (1999) Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation Blood 94:333 96 Shlomchik WD, Couzens MS, Tang CB et al (1999) Prevention of graft versus host disease by inactivation of host antigen-presenting cells Science 285:412 97 Farag SS, Bacigalupo A, Eapen M et al (2006) The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry Biol Blood Marrow Transplant 12:876 98 Ruggeri L, Mancusi A, Burchielli E et al (2007) Natural killer cell alloreactivity in allogeneic hematopoietic transplantation Curr Opin Oncol 19:142 99 Kolb HJ, Mittermuller J, Clemm C et al (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients Blood 76:2462 100 Kolb HJ, Simoes B, Schmid C (2004) Cellular immunotherapy after allogeneic stem cell transplantation in hematologic malignancies Curr Opin Oncol 16:167 101 Slavin S, Naparstek E, Nagler A et al (1996) Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation Blood 87:2195 102 Passweg JR, Stern M, Koehl U et al (2005) Use of natural killer cells in hematopoetic stem cell transplantation Bone Marrow Transplant 35:637 103 Passweg JR, Tichelli A, Meyer-Monard S et al (2004) Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation Leukemia 18:1835 104 Gonzalez S, Groh V, Spies T (2006) Immunobiology of human NKG2D and its ligands Curr Top Microbiol Immunol 298:121 105 Lundqvist A, McCoy JP, Samsel L, Childs R (2007) Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors Blood 109:3603 106 Burns LJ, Weisdorf DJ, DeFor TE et al (2003) IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial Bone Marrow Transplant 32:177 107 Law TM, Motzer RJ, Mazumdar M et al (1995) Phase III randomized trial of interleukin2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma Cancer 76:824 108 Rosenberg SA, Lotze MT, Muul LM et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer N Engl J Med 313:1485 109 Tam YK, Martinson JA, Doligosa K et al (2003) Ex vivo expansion of the highly cytotoxic human natural killer-92 cell-line under current good manufacturing practice conditions for clinical adoptive cellular immunotherapy Cytotherapy 5:259 110 Klingemann HG (2005) Natural killer cell-based immunotherapeutic strategies Cytotherapy 7:16 111 Carlens S, Gilljam M, Chambers BJ et al (2001) A new method for in vitro expansion of cytotoxic human CD3-CD56+ natural killer cells Hum Immunol 62:1092 112 Alici E, Sutlu, T, Bjorkstrand, B, et al (2008) Autologous anti-tumor activity by NK cells expanded from myeloma patients using GMP-compliant components Blood 111:3155 113 Guven H, Gilljam M, Chambers BJ et al (2003) Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy Leukemia 17:1973 Natural Killer Cells in the Treatment of Human Cancer 421 114 Fauriat C, Andersson S, Bjorklund A et al (2008) Estimation of the size of the alloreactive NK cell repertoire: studies in individuals homozygous for the group A KIR haplotype J Immunol 181:6010 115 Gattinoni L, Powell DJ Jr, Rosenberg SA et al (2006) Adoptive immunotherapy for cancer: building on success Nat Rev Immunol 6:383 116 Dudley ME, Wunderlich JR, Robbins PF et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes Science 298:850 117 Gasser S, Orsulic S, Brown EJ et al (2005) The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor Nature 436:1186 118 Gasser S, Raulet D (2006) The DNA damage response, immunity and cancer Semin Cancer Biol 16:344 119 Lundqvist A, Abrams SI, Schrump DS et al (2006) Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity Cancer Res 66:7317 120 Sayers TJ, Brooks AD, Koh CY et al (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP Blood 102:303 121 VanOosten RL, Moore JM, Karacay B et al (2005) Histone deacetylase inhibitors modulate renal cell carcinoma sensitivity to TRAIL/Apo-2L-induced apoptosis by enhancing TRAILR2 expression Cancer Biol Ther 4:1104 122 Skov S, Pedersen MT, Andresen L et al (2005) Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B Cancer Res 65:11136 123 Cebo C, Da Rocha S, Wittnebel S et al (2006) The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression, and synapse formation J Immunol 176:864 124 Boissel N, Rea D, Tieng V et al (2006) BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia J Immunol 176:5108 125 Reff ME, Carner K, Chambers KS et al (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20 Blood 83:435 126 Dall’Ozzo S, Tartas S, Paintaud G et al (2004) Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship Cancer Res 64:4664 127 Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma J Clin Oncol 21:3940 128 Pitini V, Arrigo C, Naro C et al (2007) Interleukin-2 and lymphokine-activated killer cell therapy in patients with relapsed B-cell lymphoma treated with rituximab Clin Cancer Res 13:5497 129 Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer Nat Biotechnol 23:1147 130 Carter PJ (2006) Potent antibody therapeutics by design Nat Rev Immunol 6:343 131 Shahied LS, Tang Y, Alpaugh RK et al (2004) Bispecific minibodies targeting HER2/neu and CD16 exhibit improved tumor lysis when placed in a divalent tumor antigen binding format J Biol Chem 279:53907 132 Hartmann F, Renner C, Jung W et al (2001) Anti-CD16/CD30 bispecific antibody treatment for Hodgkin’s disease: role of infusion schedule and costimulation with cytokines Clin Cancer Res 7:1873 133 Slavin S (2005) Allogeneic cell-mediated immunotherapy at the stage of minimal residual disease following high-dose chemotherapy supported by autologous stem cell transplantation Acta Haematol 114:214 Index A B Acceptance, 222, 224, 226, 228 Activation receptors, 406–408, 411–415 Adaptive immunity, 316, 321 Adoptive cell therapy, 412–414 Adoptive immunotherapy, 210, 212 Adoptive transfer, 209–212 Adoptive transfer of NK-92 cells, 212 Allergy, 191–196 Allogeneic bone marrow cells, 201, 203 Allogeneic HSCT, 200, 201, 203–205, 209, 210 Alopecia, 259–260 Amplification, 394 Antibody dependent cellular cytotoxicity (ADCC), 9, 17, 18, 346, 348, 349 Anti-CD20, 233 Anti-CD52, 233 Antimicrobial proteins/peptides cathelicidin(s), 159 defensin(s), 158, 159, 161 granulysin, 158, 159, 162 Antiphospholipid syndrome, 243, 245 Areata, 259–260 Asthma, 191–196 Atopy, 255–257 Autoantibodies, 355–357 Autoimmune diseases, 178–186, 241–251 Autoimmunity, 177–186, 375, 377–379 Autologous, 200, 206 2B4, 11–13, 15, 18, 30 Bacteria, 303–308 Bordetella pertussis, 154 Escherichia coli, 155, 158, 167, 168 Franciscella tularensis, 158 Helicobacter pylori, 170 Klebsiella pneumoniae, 161 Legionella pneumophilia, 154, 169 Listeria innocua, 159 Listeria monocytogenes, 155, 157, 158, 169, 170 Mycobacterium avium, 155, 156, 158 Mycobacterium bovis, 157, 161 Mycobacterium tuberculoisis, 155, 158, 159, 165–167, 169, 170 Pseudomonas aeruginosa, 155 Salmonella enteritidis, 156 Salmonella minesota, 167 Salmonella typhimurium, 158, 169 Staphylococcus aureus, 154, 155, 158, 169 Streptococcus pneumoniae, 155 Yersinia pestis, 170 B cell receptor, 346, 349 Bone marrow, 200–201, 203, 210, 212 Bone marrow transplantation, 201, 212 Bronchiolitis obliterans syndrome, 232 B6.Sle1b, 356 C Cancer, 25–26, 31, 267, 268, 332, 334–336 Cardiac allograft vasculopathy (CAV), 225 423 424 CCL9, 226 CCL10, 226 CCL11, 227 CCR1, 227 CCR4, 226, 227 CCR7, 301, 302, 306 CD2, 7, 9, 11, 12, 17, 18 CD16, 5, 6, 8–11, 18–20, 23–24, 26–28 CD27, 27–29 CD48, 12–13, 30, 354, 356, 361–363 CD56, 317, 319 CD69, 352, 354, 357 CD86, 357, 358 CD117, 6–8, 29 CD154, 227 CD244, 354, 356, 361 CD56bright, 5–8, 10, 16, 19, 28, 301, 302, 304, 307, 308 CD28 costimulation, 224 CD95L, 26 cDNA, 393, 394 CD94/NKG2C, 11, 20 CD94/NKG2 family, 128, 132, 134 CD4+ T cells, 371–375, 381 CFSE, 354, 358, 359 Chemokine receptors, 226–227 Chemokines, 222, 226–228, 315–320 Cis interaction, 93–106 Combination therapy, 414–415 Conditioning, 200, 201, 203, 206, 207, 209, 211, 213 Cord blood, 200–201 Cord blood transplantation, 201 Costimulatory molecules, 320, 321 Coxackie virus, 182 cRNA, 393 CTL response, 370–372 Cutaneous lymphomas, 257 CXCL16, 229 CXCR3, 226 CXCR6, 229 Cyclosporin A, 227, 233 Cytokine circuit, 347, 348, 350–352, 356 Cytokines, 40–41, 44, 45, 52, 154, 156–166, 168–171, 178, 180, 182, 183, 186, 392, 396, 398–402, 405, 408, 409, 413 complexes, 212 IFN-a, 161, 164 Index IFN-g, 154, 157, 161, 164 IL-2, 159, 163 IL-12, 154, 161, 162, 163, 164, 169, 171 IL-18, 162, 169 IL-1b, 161, 163 production, 180, 182, 183 TGF-b, 159 TNF-a, 157, 158, 161 Cytomegalovirus, 348 Cytotoxicity, 267 Fas, 158, 162 granzymes, 158 perforin, 158, 159, 162 TRAIL R, 158 D DAP10, 11–12 DAP12, 11, 18, 20, 22, 28, 183 Dendritic cells (DC), 316–319, 321–323, 330–338, 369–375, 379–380, 382 autoimmune diseases, 241–251 lupus erythematosus, 249–250 Depletion, 181–183 Diabetes, 178, 181–182, 186, 376, 378, 379 DNAM-1, 21, 319, 323 Donor lymphocyte infusions (DLI), 411 E EAT-2, 30 Effector mechanisms, 408, 414 Encephalomyelitis (EAE), 377 ERT, 30 Experimental autoimmune encephalomyelitis (EAE), 183 F FceRI-g, 11, 28 FcgRIII, 11 Foxp3, 369, 374 G Gene activity, 393–395 array, 393–396, 399, 400, 402 expression, 393–396, 399–402 Index profile, 393, 395, 396, 399, 402 regulation, 393, 399, 401 Gene therapy, 211–212 Germline, 357–361 Germline transcripts, 357, 360, 361 GPI-anchored receptor, 361 gpUL18, 130–131 gpUL40, 134 Graft-versus-host disease (GVHD), 200, 201, 203, 205, 206, 208–210, 323 Granulocyte-macrophage colonystimulating factor (GM-CSF), 12, 16 425 Immunoreceptor tyrosine-based activation motif (ITAM), 10–12, 18, 22, 28 Immunoreceptor tyrosine-based inhibitory motifs (ITIM), 14, 15, 18, 22, 28, 126, 144 Immunosuppressants, 232 Immunotherapies, 210–213 Inflammatory diseases, 241–251 Inflammatory myopathy, 246 Influenza, 21 Inhibitory receptors, 126–128, 131, 134, 135, 140, 144, 407–408, 410 Islets, 181, 182 H Hematopoietic stem cells (HSC), 200–201, 203, 204, 208 Hematopoietic stem cell transplantation (HSCT), 199, 208, 211, 212, 410–411 allogeneic, 200, 201, 203–205, 209, 210 conditioning, 201, 206, 207 Hepatitis, 375–377 Herpes simplex virus, 261–262 HIV, 22 HLA-G, 112, 113, 116–119 Homeostasis, 316, 321, 323 I IFN-b, 20 IFN-g, 2, 5–8, 10, 12–14, 16–17, 19, 22–26, 28, 30, 315–321, 347–353, 358, 360–362 IgG2a/c, 346, 347 Ig-like transcripts (ILT), 128 IL-4+, 24 IL-5, 317, 319 IL-10, 24–25, 317, 323 IL-12, 14, 16–18, 21, 23–26, 303, 308, 309, 347, 350–353, 362 IL-13, 362–363 IL-15, 4–7, 12, 16, 19, 23, 29 IL-18, 16–18, 23, 25, 26, 353, 362 IL-22, 318 IL-15 cDNA, 211–212 Immune homeostasis, 369–370, 374–375, 380, 383 Immune regulation, 120 Immune tolerance, 369, 374, 381 K K5, 134, 140, 141 Killer cell immunoglobulin-like receptors (KIR), 5, 6, 8, 11, 14, 15, 19, 21, 22, 25, 26, 127, 128, 144, 182, 186, 221–234 genes, 276–278, 281, 282, 286, 289, 290 genotypes, autoimmune and inflammatory diseases, 244–245 haplotypes, 63–89, 276, 281, 286, 290 inhibitor, 276–278, 281, 283, 284, 286, 287 KIR A haplotype, 287 KIR B haplotype, 288, 289 KIR2DL3, 276–278, 284, 286, 288 KIR2DL4, 277, 286, 287 KIR3DS1, 278, 281, 283, 288 ligands, 277, 278, 284, 286, 288, 289, 290 polymorphism, 72, 79, 84, 86 population frequencies, 67–71, 79, 80, 83, 89 Killer immunoglobulin-like receptors (KIR), 374–375, 378–379, 381 Kinetics, 395, 402 KIR2DL1, 230, 231 KIR2DL4, 19 KIR3DL2, 230 KIR2DL2/2DL3, 230 KIR2DS4, 230 KIR-ligand mismatch, 410, 411, 415 L Leukemia, 267, 269–273 LFA-1, 9, 17, 18 426 LFA-1/ICAM-1, 228 Licensing, 205 Listeria monocytogenes, 350 Liver injury, 375–377 Location, 180, 181, 185 LTb receptor (LTbR), 29 Lupus erythematosus, 242, 243, 249–250 Ly49, 127, 128, 134, 143, 144 Ly49A, 96–106 Ly49H, 127, 143, 144, 348 Lymph nodes, 2, 3, 5–9, 316–317 Lymphocyte function-associated antigen-1 (LFA-1), 227 Lymphoma, 267, 269–273 Lymphoproliferative diseases, 244 Ly49P, 127, 134, 144 Ly49 receptor, 27 M m04, 127, 133, 134, 144 m06, 133, 134 m144, 132, 133 m152, 133, 134, 139 m157, 127, 143 Macrophages, 180, 182 Major histocompatibility complex (MHC) class I, 185 group HLA-C, 277–278, 284, 287–288 HLA-BBw4, 277, 283–284 HLA-G, 286 homologues, 130–133 receptor, automimmune/inflammatory diseases, 245–246 MCP-1/CX3CL1, 226 Membrane transfers, 111–119 Methylprednisolone, 233 m138/fcr-1, 139 MICA and MICB, 140 Mice, 4, 11, 12, 14, 27, 29, 30 Microenvironment, 185 MicroRNA, 142–143 Missing self, 126, 129, 134, 135 Missing self hypothesis, 126, 135 Missing-self reactivity, 415 mRNA, 394, 395, 402 Multiple sclerosis (MS), 182–183 Index Myasthenia gravis, 180 Mycobacteria, 23 N Natural cytotoxicity receptors (NCRs) NKp30, 164, 165 NKp44, 164, 165 NKp46, 164, 165 Natural killer (NK) cells, 93–106, 109–121, 177–186, 267–274 activating and inhibitory receptors, 136 alloreactive, 200, 205–207 autoimmune and inflammatory diseases, 241–251 definition, 405–406 development, 39–54 differentiation, 39–54 identification, 405, 407, 415 inhibitory receptor blockade, 211 lupus erythematosus, 249–250 receptor gene, 212 responses, 180, 186 Treg, 247–249 NCR receptors, 13 Negative factor (Nef), 134, 140 NK1, 192–196 NK2, 192–196 NK cell ligands AICL, 165, 167 CD48, 166, 167 LLT-1, 166 MICA/B, 162, 167, 168 ULBP(s), 159, 162, 167, 168 vimentin, 15, 162, 167 NK cell subsets, 380–383 NKG2D, 128–129, 138–141, 143, 315, 318–323, 371, 373, 374, 376–377, 381 NKG2D ligands (NKG2DLs), 129, 138–141, 322, 323 NKp30, 129, 137, 138, 319, 320, 323 NKp46, 318, 320, 321, 373–375, 381, 382 NKR-P1 family, 129, 144 NOD mice, 181, 182, 184 O Organ-specific, 178, 181–182, 185 OX40L, 318–320 Index 427 P S Pancreas, 178, 181, 182, 184–186 Pathogen-associated molecular patterns (PAMPs), 13 CpG DNA, 163 D-g-glutamyl-meso-DAP, 163–164 flagellin, 162, 163 KpOmpA, 161, 163 LPS, 167, 168 ManLAM, 170 muramyl dipeptide (MDP), 162, 164 poly (I:C), 167 R848, 163 Pattern recognition receptors (PRRs ) DC-SIGN, 170–171 Nod-like receptors (NLRs), 160, 162 Toll-like receptors (TLRs), 160, 162 Pemphigus vulgaris, 183, 243, 249 Perforin, 301, 302, 307, 308 Peripheral blood, 200–202, 205, 206 Plasmodium falciparum, 25 Poly(I:C), 347, 348, 350, 352, 362 Polyclonal antithymocyte globulin (rATG), 233 Polyclonal B cell response, 351 Polyoma virus, 349 pp65, 135–138 Preclinical models, 39 Pregnancy, 243, 245 Protein analysis, 396, 397 array, 393, 395–399, 402 expression, 395, 400, 402 level, 395, 400, 402 Protozoan infections, 23–25 Psoriasis, 243, 261 Secondary lymphoid organs, 301–302, 305 lymph node, 299, 302, 304, 306–308 tonsil, 302 Sentinels, 180 Severe combined immune deficient (SCID), 348 SH2D1A/DSHP/SAP gene, 356 Sjoăgrens syndrome, 184, 250 SLAM/CD2, 356 Spondylarthropathies, 243, 250 Subsets, 178, 182, 1848–186 Supramolecular activating clusters (SMAC), 27 Supramolecular inhibitory clusters (SMIC), 27 Switch recombination, 346, 358–361, 363 Systemic, 178, 182, 183, 185 Systemic Lupus Erythematosis (SLE), 178, 183 Systemic sclerosis, 243–245 R Rapamycin, 226, 233 Receptors, 125–145, 405–415 Reconstitution, 200, 201, 207–211 Regulatory T (Treg) cells, 26, 318, 320–322, 329–338, 369, 374 Rejection, 200, 201, 203–206, 209, 221, 222, 224–232 Renal tubular epithelial cells, 225 Rheumatoid arthritis (RA), 178, 182, 243, 250 T T cells, 179–184, 302, 306, 315–324 memory, 354–355 polarization, 300, 308–309 response, 300 T-dependent antigen, 353, 354 TGF-b, 317, 323 T helper (Th1) cells, 316–318 T-independent (TI) antigen, 346–347, 349–352, 356, 360, 361 Tissues, 180, 185 TLR, 13–14, 18, 25 TLR2, 350, 352, 353 TLR3, 347, 348, 350 TLR4, 350, 353 TLR7, 349 TNF-a, 2, 10, 13–14, 16, 24, 26 Tolerance, 222, 227–230 Transcription factors, 39–41 Transforming growth factor (TGF-b), 14, 24–26 Transporter associated with antigen processing (TAP), 132 Trogocytosis, 108–121 Tumor cells, 405–410, 414 428 Index Tumor necrosis factor (TNF), 299, 301, 305, 307–309 US11, 132–134 Uterine NK (uNK) cells, 379–380 U V UL142, 140 UL16-binding proteins (ULBP), 374 Ulcerative colitis, 243, 246 US2, 132–135 US6, 132–134 Varicella zoster virus (VZV), 21 Viruses, 3, 12, 13, 16, 19–22, 26, 30 W www.allelefrequencies.net, 68, 71, 79, 82 .. .Natural Killer Cells Jacques Zimmer Editor Natural Killer Cells At the Forefront of Modern Immunology Editor Dr Jacques Zimmer Centre de Recherche Public de... Brasil, 35400-000 J Zimmer (ed.), Natural Killer Cells, DOI 10.1007/978-3-642-02309-5_1, # Springer-Verlag Berlin Heidelberg 2010 V.P.C.P de Toledo et al Introduction Natural killer (NK) cells represent... Nassim Dali-Youcef, Jean-Robert Harle, Jacques Zimmer, and Emmanuel Andres Natural Killer Cells and the Skin 255 Dagmar von Bubnoff NK Cells in Oncology