Abstract
Cell contact-dependent inhibition and regulation of immune responses play an essential role in balancing the need for rapid and efficient responses to a wide variety of pathological challenges, while at the same time maintaining self-tolerance. Much attention has been given to immune synapses that lead to the activation of, for example, cell-mediated cytotoxicity, and here we compare the supramolecular dynamics of synapses that lead to inhibition or regulatory functions. We focus on natural killer cells where such different synapses have been best studied. An emergent principle is that inhibition or regulatory responses are commonly achieved by selective recruitment of signalling proteins to the synapse and exclusion of membrane-proximal intracellular proteins needed for activation. We also discuss evidence that an inhibitory synapse triggers or maintains effector cells in a migratory configuration, which serves to break the synapse before the steps needed for effector cell activation can be completed. This model implies that the concept of kinetic-proofreading, previously used to describe activation of individual T-cell receptors, can also apply in determining the outcome of intercellular conjugation.
References
Almeida CR, Davis DM (2006) Segregation of HLA-C from ICAM-1 at NK cell immune synapses is controlled by its cell surface density. J Immunol 177:6904–6910
Andoniou CE, Coudert JD, Degli-Esposti MA (2008) Killers and beyond: NK-cell-mediated control of immune responses. Eur J Immunol 38:2938–2942
Bhat R, Watzl C (2007) Serial killing of tumor cells by human natural killer cells – enhancement by therapeutic antibodies. PLoS ONE 2:e326
Bhat R, Eissmann P, Endt J, Hoffmann S, Watzl C (2006) Fine-tuning of immune responses by SLAM-related receptors. J Leukoc Biol 79:417–424
Blery M, Delon J, Trautmann A, Cambiaggi A, Olcese L, Biassoni R, Moretta L, Chavrier P, Moretta A, Daeron M et al (1997) Reconstituted killer cell inhibitory receptors for major histocompatibility complex class I molecules control mast cell activation induced via immunoreceptor tyrosine-based activation motifs. J Biol Chem 272:8989–8996
Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W et al (2004) NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 104:3267–3275
Brilot F, Strowig T, Roberts SM, Arrey F, Munz C (2007) NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha. J Clin Invest 117:3316–3329
Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91
Bunnell SC, Hong DI, Kardon JR, Yamazaki T, McGlade CJ, Barr VA, Samelson LE (2002) T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J Cell Biol 158:1263–1275
Burshtyn DN, Shin J, Stebbins C, Long EO (2000) Adhesion to target cells is disrupted by the killer cell inhibitory receptor. Curr Biol 10:777–780
Campi G, Varma R, Dustin ML (2005) Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med 202:1031–1036
Carbone E, Terrazzano G, Ruggiero G, Zanzi D, Ottaiano A, Manzo C, Karre K, Zappacosta S (1999) Recognition of autologous dendritic cells by human NK cells. Eur J Immunol 29:4022–4029
Carlin LM, Eleme K, McCann FE, Davis DM (2001) Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses. J Exp Med 194:1507–1517
Cemerski S, Das J, Giurisato E, Markiewicz MA, Allen PM, Chakraborty AK, Shaw AS (2008) The balance between T cell receptor signaling and degradation at the center of the immunological synapse is determined by antigen quality. Immunity 29:414–422
Chouaib S, Thiery J, Gati A, Guerra N, El Behi M, Dorothee G, Mami-Chouaib F, Bellet D, Caignard A (2002) Tumor escape from killing: role of killer inhibitory receptors and acquisition of tumor resistance to cell death. Tissue Antigens 60:273–281
Culley FJ, Johnson M, Evans JH, Kumar S, Crilly R, Casasbuenas J, Schnyder T, Mehrabi M, Deonarain MP, Ushakov DS et al (2009) Natural killer cell signal integration balances synapse symmetry and migration. PLoS Biol 7:e1000159
Daeron M, Jaeger S, Du Pasquier L, Vivier E (2008) Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol Rev 224:11–43
Davis DM (2002) Assembly of the immunological synapse for T cells and NK cells. Trends Immunol 23:356–363
Davis DM (2006) Intrigue at the immune synapse. Sci Am 294:48–55
Davis DM (2007) Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nat Rev Immunol 7:238–243
Davis DM (2009) Are we done yet? Mechanisms and functions for the duration of intercellular contacts made by lymphocytes. Nat Rev Immunol (in press)
Davis DM, Dustin ML (2004) What is the importance of the immunological synapse? Trends Immunol 25:323–327
Davis SJ, van der Merwe PA (1996) The structure and ligand interactions of CD2: implications for T-cell function. Immunol Today 17:177–187
Davis SJ, van der Merwe PA (2006) The kinetic-segregation model: TCR triggering and beyond. Nat Immunol 7:803–809
Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL (1999) The human natural killer cell immune synapse. Proc Natl Acad Sci USA 96:15062–15067
Dietrich J, Cella M, Colonna M (2001) Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. J Immunol 166:2514–2521
Dustin ML (2008a) Hunter to gatherer and back: immunological synapses and kinapses as variations on the theme of amoeboid locomotion. Annu Rev Cell Dev Biol 24:577–596
Dustin ML (2008b) T-cell activation through immunological synapses and kinapses. Immunol Rev 221:77–89
Dustin ML, Bromley SK, Kan Z, Peterson DA, Unanue ER (1997) Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc Natl Acad Sci USA 94:3909–3913
Egen JG, Allison JP (2002) Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16:23–35
Eissmann P, Beauchamp L, Wooters J, Tilton JC, Long EO, Watzl C (2005) Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 105:4722–4729
Endt J, McCann FE, Almeida CR, Urlaub D, Leung R, Pende D, Davis DM, Watzl C (2007) Inhibitory receptor signals suppress ligation-induced recruitment of NKG2D to GM1-rich membrane domains at the human NK cell immune synapse. J Immunol 178:5606–5611
Eriksson M, Leitz G, Fallman E, Axner O, Ryan JC, Nakamura MC, Sentman CL (1999a) Inhibitory receptors alter natural killer cell interactions with target cells yet allow simultaneous killing of susceptible targets. J Exp Med 190:1005–1012
Eriksson M, Ryan JC, Nakamura MC, Sentman CL (1999b) Ly49A inhibitory receptors redistribute on natural killer cells during target cell interaction. Immunology 97:341–347
Fan QR, Long EO, Wiley DC (2000) Cobalt-mediated dimerization of the human natural killer cell inhibitory receptor. J Biol Chem 275:23700–23706
Fassett MS, Davis DM, Valter MM, Cohen GB, Strominger JL (2001) Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering. Proc Natl Acad Sci USA 98:14547–14552
Faure M, Barber DF, Takahashi SM, Jin T, Long EO (2003) Spontaneous clustering and tyrosine phosphorylation of NK cell inhibitory receptor induced by ligand binding. J Immunol 170:6107–6114
Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195:343–351
Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5:405–411
Fernandez-Suarez M, Ting AY (2008) Fluorescent probes for super-resolution imaging in living cells. Nat Rev Mol Cell Biol 9:929–943
Fourmentraux-Neves E, Jalil A, Da Rocha S, Pichon C, Chouaib S, Bismuth G, Caignard A (2008) Two opposite signaling outputs are driven by the KIR2DL1 receptor in human CD4+ T cells. Blood 112:2381–2389
Guerra N, Michel F, Gati A, Gaudin C, Mishal Z, Escudier B, Acuto O, Chouaib S, Caignard A (2002) Engagement of the inhibitory receptor CD158a interrupts TCR signaling, preventing dynamic membrane reorganization in CTL/tumor cell interaction. Blood 100:2874–2881
Harwood NE, Batista FD (2008) New insights into the early molecular events underlying B cell activation. Immunity 28:609–619
Henel G, Singh K, Cui D, Pryshchep S, Lee WW, Weyand CM, Goronzy JJ (2006) Uncoupling of T-cell effector functions by inhibitory killer immunoglobulin-like receptors. Blood 107:4449–4457
Inoue H, Miyaji M, Kosugi A, Nagafuku M, Okazaki T, Mimori T, Amakawa R, Fukuhara S, Domae N, Bloom ET et al (2002) Lipid rafts as the signaling scaffold for NK cell activation: tyrosine phosphorylation and association of LAT with phosphatidylinositol 3-kinase and phospholipase C-gamma following CD2 stimulation. Eur J Immunol 32:2188–2198
Karre K, Ljunggren HG, Piontek G, Kiessling R (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675–678
Krzewski K, Strominger JL (2008) The killer's kiss: the many functions of NK cell immunological synapses. Curr Opin Cell Biol 20:597–605
Krzewski K, Chen X, Orange JS, Strominger JL (2006) Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. J Cell Biol 173:121–132
Kubin MZ, Parshley DL, Din W, Waugh JY, Davis-Smith T, Smith CA, Macduff BM, Armitage RJ, Chin W, Cassiano L et al (1999) Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48. Eur J Immunol 29:3466–3477
Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274
Lee KH, Holdorf AD, Dustin ML, Chan AC, Allen PM, Shaw AS (2002) T cell receptor signaling precedes immunological synapse formation. Science 295:1539–1542
Lee KH, Dinner AR, Tu C, Campi G, Raychaudhuri S, Varma R, Sims TN, Burack WR, Wu H, Wang J et al (2003) The immunological synapse balances T cell receptor signaling and degradation. Science 302:1218–1222
LeMaoult J, Caumartin J, Carosella ED (2007) Exchanges of membrane patches (trogocytosis) split theoretical and actual functions of immune cells. Hum Immunol 68:240–243
Ljunggren HG, Karre K (1990) In search of the “missing self”: MHC molecules and NK cell recognition. Immunol Today 11:237–244
Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904
Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84
Lou Z, Jevremovic D, Billadeau DD, Leibson PJ (2000) A balance between positive and negative signals in cytotoxic lymphocytes regulates the polarization of lipid rafts during the development of cell-mediated killing. J Exp Med 191:347–354
Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647
Martz E (1976) Multiple target cell killing by the cytolytic T lymphocyte and the mechanism of cytotoxicity. Transplantation 21:5–11
Masilamani M, Nguyen C, Kabat J, Borrego F, Coligan JE (2006) CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J Immunol 177:3590–3596
McCann FE, Suhling K, Carlin LM, Eleme K, Taner SB, Yanagi K, Vanherberghen B, French PM, Davis DM (2002) Imaging immune surveillance by T cells and NK cells. Immunol Rev 189:179–192
McCann FE, Vanherberghen B, Eleme K, Carlin LM, Newsam RJ, Goulding D, Davis DM (2003) The size of the synaptic cleft and distinct distributions of filamentous actin, ezrin, CD43, and CD45 at activating and inhibitory human NK cell immune synapses. J Immunol 170:2862–2870
McKeithan TW (1995) Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci USA 92:5042–5046
McMahon CW, Raulet DH (2001) Expression and function of NK cell receptors in CD8+ T cells. Curr Opin Immunol 13:465–470
Moretta L, Ferlazzo G, Bottino C, Vitale M, Pende D, Mingari MC, Moretta A (2006) Effector and regulatory events during natural killer-dendritic cell interactions. Immunol Rev 214:219–228
Nakajima H, Cella M, Langen H, Friedlein A, Colonna M (1999) Activating interactions in human NK cell recognition: the role of 2B4-CD48. Eur J Immunol 29:1676–1683
Nedvetzki S, Sowinski S, Eagle RA, Harris J, Vely F, Pende D, Trowsdale J, Vivier E, Gordon S, Davis DM (2007) Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses. Blood 109:3776–3785
Newman KC, Riley EM (2007) Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens. Nat Rev Immunol 7:279–291
Oddos S, Dunsby C, Purbhoo MA, Chauveau A, Owen DM, Neil MAA, Davis DM, French PMW (2008) High-speed high-resolution imaging of intercellular immune synapses using optical tweezers. Biophys J 95:L66–L68
Orange JS (2008) Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol 8:713–725
Orange JS, Ramesh N, Remold-O’Donnell E, Sasahara Y, Koopman L, Byrne M, Bonilla FA, Rosen FS, Geha RS, Strominger JL (2002) Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci USA 99:11351–11356
Orange JS, Harris KE, Andzelm MM, Valter MM, Geha RS, Strominger JL (2003) The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc Natl Acad Sci USA 100:14151–14156
Pallandre JR, Krzewski K, Bedel R, Ryffel B, Caignard A, Rohrlich PS, Pivot X, Tiberghien P, Zitvogel L, Strominger JL et al (2008) Dendritic cell and natural killer cell cross-talk: a pivotal role of CX3CL1 in NK cytoskeleton organization and activation. Blood 112:4420–4424
Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, Ochs HD, Wolf H, Bonnefoy JY, Biassoni R et al (2000) X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 192:337–346
Peggs KS, Quezada SA, Allison JP (2008) Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev 224:141–165
Pritchard NR, Smith KG (2003) B cell inhibitory receptors and autoimmunity. Immunology 108:263–273
Rajagopalan S, Long EO (1998) Zinc bound to the killer cell-inhibitory receptor modulates the negative signal in human NK cells. J Immunol 161:1299–1305
Rajagopalan S, Long EO (2005) Understanding how combinations of HLA and KIR genes influence disease. J Exp Med 201:1025–1029
Rajagopalan S, Winter CC, Wagtmann N, Long EO (1995) The Ig-related killer cell inhibitory receptor binds zinc and requires zinc for recognition of HLA-C on target cells. J Immunol 155:4143–4146
Raulet DH (2004) Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 5:996–1002
Sanni TB, Masilamani M, Kabat J, Coligan JE, Borrego F (2004) Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. Mol Biol Cell 15:3210–3223
Schleinitz N, March ME, Long EO (2008) Recruitment of activation receptors at inhibitory NK cell immune synapses. PLoS ONE 3:e3278
Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (2006) Reversal of the TCR stop signal by CTLA-4. Science 313:1972–1975
Schneider H, Smith X, Liu H, Bismuth G, Rudd CE (2008) CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur J Immunol 38:40–47
Seminario MC, Bunnell SC (2008) Signal initiation in T-cell receptor microclusters. Immunol Rev 221:90–106
Semino C, Angelini G, Poggi A, Rubartelli A (2005) NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 106:609–616
Sims TN, Soos TJ, Xenias HS, Dubin-Thaler B, Hofman JM, Waite JC, Cameron TO, Thomas VK, Varma R, Wiggins CH et al (2007) Opposing effects of PKCtheta and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129:773–785
Sivori S, Falco M, Marcenaro E, Parolini S, Biassoni R, Bottino C, Moretta L, Moretta A (2002) Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc Natl Acad Sci USA 99:4526–4531
Snyder MR, Muegge LO, Offord C, O’Fallon WM, Bajzer Z, Weyand CM, Goronzy JJ (2002) Formation of the killer Ig-like receptor repertoire on CD4+CD28null T cells. J Immunol 168:3839–3846
Sohn HW, Pierce SK, Tzeng SJ (2008) Live cell imaging reveals that the inhibitory FcgammaRIIB destabilizes B cell receptor membrane-lipid interactions and blocks immune synapse formation. J Immunol 180:793–799
Spaggiari GM, Carosio R, Pende D, Marcenaro S, Rivera P, Zocchi MR, Moretta L, Poggi A (2001) NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46. Eur J Immunol 31:1656–1665
Springer TA (1990) Adhesion receptors of the immune system. Nature 346:425–434
Standeven LJ, Carlin LM, Borszcz P, Davis DM, Burshtyn DN (2004) The actin cytoskeleton controls the efficiency of killer Ig-like receptor accumulation at inhibitory NK cell immune synapses. J Immunol 173:5617–5625
Stebbins CC, Watzl C, Billadeau DD, Leibson PJ, Burshtyn DN, Long EO (2003) Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol Cell Biol 23:6291–6299
Strowig T, Brilot F, Munz C (2008) Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity. J Immunol 180:7785–7791
Tangye SG, Lazetic S, Woollatt E, Sutherland GR, Lanier LL, Phillips JH (1999) Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J Immunol 162:6981–6985
Treanor B, Lanigan PM, Kumar S, Dunsby C, Munro I, Auksorius E, Culley FJ, Purbhoo MA, Phillips D, Neil MA et al (2006) Microclusters of inhibitory killer immunoglobulin-like receptor signaling at natural killer cell immunological synapses. J Cell Biol 174:153–161
Tsai RK, Discher DE (2008) Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J Cell Biol 180:989–1003
Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS (2008) TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205:233–244
Ugolini S, Vivier E (2000) Regulation of T cell function by NK cell receptors for classical MHC class I molecules. Curr Opin Immunol 12:295–300
Vales-Gomez M, Erskine RA, Deacon MP, Strominger JL, Reyburn HT (2001) The role of zinc in the binding of killer cell Ig-like receptors to class I MHC proteins. Proc Natl Acad Sci USA 98:1734–1739
van Bergen J, Thompson A, van der Slik A, Ottenhoff TH, Gussekloo J, Koning F (2004) Phenotypic and functional characterization of CD4 T cells expressing killer Ig-like receptors. J Immunol 173:6719–6726
Varma R, Campi G, Yokosuka T, Saito T, Dustin ML (2006) T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25:117–127
Vyas YM, Mehta KM, Morgan M, Maniar H, Butros L, Jung S, Burkhardt JK, Dupont B (2001) Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J Immunol 167:4358–4367
Vyas YM, Maniar H, Dupont B (2002) Cutting edge: differential segregation of the SRC homology 2-containing protein tyrosine phosphatase-1 within the early NK cell immune synapse distinguishes noncytolytic from cytolytic interactions. J Immunol 168:3150–3154
Vyas YM, Maniar H, Lyddane CE, Sadelain M, Dupont B (2004) Ligand binding to inhibitory killer cell Ig-like receptors induce colocalization with Src homology domain 2-containing protein tyrosine phosphatase 1 and interruption of ongoing activation signals. J Immunol 173:1571–1578
Watzl C, Long EO (2003) Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4 (CD244) to lipid rafts. J Exp Med 197:77–85
Wulfing C, Purtic B, Klem J, Schatzle JD (2003) Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing. Proc Natl Acad Sci USA 100:7767–7772
Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A, Tokunaga M, Dustin ML, Saito T (2005) Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat Immunol 6:1253–1262
Acknowledgements
We thank current members of our laboratory and F.J. Culley, M.A. Purbhoo, F.V. de Abreu, P.M.W. French, M.A.A. Neil and A.I. Magee for useful discussions. We thank N. Powell for assistance with preparing the figures. Research in our laboratory is funded by The Medical Research Council, The Biotechnology and Biological Sciences Research Council, The Wellcome Trust, a Lister Institute Research Prize and a Wolfson Royal Society Research Merit Award (to DMD).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Eissmann, P., Davis, D.M. (2010). Inhibitory and Regulatory Immune Synapses. In: Saito, T., Batista, F. (eds) Immunological Synapse. Current Topics in Microbiology and Immunology, vol 340. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-03858-7_4
Download citation
DOI: https://doi.org/10.1007/978-3-642-03858-7_4
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-03857-0
Online ISBN: 978-3-642-03858-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)