Early interactions between natural killer (NK) and dendritic cells (DC) shape the immune response at the frontier of innate and adaptive immunity. Activated NK cells participate in maturation or deletion of DCs that remain immature. We previously demonstrated that infection with a high virulence (HV) population of the protozoan parasite Trypanosoma cruzi downmodulates DC maturation and T-cell activation capacity. Here, we evaluated the role of NK cells in regulating the maturation level of DCs. Shortly after infection with HV T. cruzi, DCs in poor maturation status begin to accumulate in mouse spleen. Although infection induces NK cell cytotoxicity and cytokine production, NK cells from mice infected with HV T. cruzi exhibit reduced ability to lyse and fail to induce maturation of bone marrow-derived immature DCs (iDCs). NK-mediated lysis of iDCs is restored by in vitro blockade of the IL-10 receptor during NK-DC interaction or when NK cells are obtained from T. cruzi-infected IL-10 knockout mice. These results suggest that infection with a virulent T. cruzi strain alters NK cell-mediated regulation of the adaptive immune response induced by DCs. This regulatory circuit where IL-10 appears to participate might lead to parasite persistence but can also limit the induction of a vigorous tissue-damaging T-cell response.

Keywords:
Crosstalk, Cytotoxicity, Dendritic cells, Natural killer cells, Parasites, Protozoan, Trypanosoma cruzi
1.
Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, et al: Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002;195:343-351.
2.
Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, et al: Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002;195:327-333.
3.
Piccioli D, Sbrana S, Melandri E, Valiante NM: Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002;195:335-341.
4.
Chambers BJ, Salcedo M, Ljunggren HG: Triggering of natural killer cells by the costimulatory molecule CD80 (B7-1). Immunity 1996;5:311-317.
5.
Wilson JL, Heffler LC, Charo J, Scheynius A, Bejarano MT, et al: Targeting of human dendritic cells by autologous NK cells. J Immunol 1999;163:6365-6370.
6.
Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E: Natural-killer cells and dendritic cells: ‘l'union fait la force'. Blood 2005;106:2252-2258.
7.
Morandi B, Mortara L, Chiossone L, Accolla RS, Mingari MC, et al: Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response. PLoS One 2012;7:e39170.
8.
Pan American Health Organization: Health in the Americas 2007. Regional, Scientific, and Technical Publication 622. Washington, Pan American Health Organization, 2007, http://www.paho.org/hia/index.html.
9.
Gonzalez Cappa SM, Mirkin GA, Solana ME, Tekiel VS: Trypanosoma cruzi pathology. Strain dependent (in Spanish)? Medicina (B Aires) 1999;59:69-74.
10.
Macedo AM, Machado CR, Oliveira RP, Pena SD: Trypanosoma cruzi: genetic structure of populations and relevance of genetic variability to the pathogenesis of Chagas disease. Mem Inst Oswaldo Cruz 2004;99:1-12.
11.
Cardillo F, Voltarelli JC, Reed SG, Silva JS: Regulation of Trypanosoma cruzi infection in mice by gamma interferon and interleukin 10: role of NK cells. Infect Immun 1996;64:128-134.
12.
Antunez MI, Cardoni RL: Trypanosoma cruzi: the expansion of NK, T, and NKT cells in the experimental infection. Exp Parasitol 2004;106:85-94.
13.
Lieke T, Steeg C, Graefe SE, Fleischer B, Jacobs T: Interaction of natural killer cells with Trypanosoma cruzi-infected fibroblasts. Clin Exp Immunol 2006;145:357-364.
14.
Lieke T, Graefe SE, Klauenberg U, Fleischer B, Jacobs T: NK cells contribute to the control of Trypanosoma cruzi infection by killing free parasites by perforin-independent mechanisms. Infect Immun 2004;72:6817-6825.
15.
Abrahamsohn IA, Coffman RL: Cytokine and nitric oxide regulation of the immunosuppression in Trypanosoma cruzi infection. J Immunol 1995;155:3955-3963.
16.
Kierszenbaum F, de Diego JL, Fresno M, Sztein MB: Inhibitory effects of the Trypanosoma cruzi membrane glycoprotein AGC10 on the expression of IL-2 receptor chains and secretion of cytokines by subpopulations of activated human T lymphocytes. Eur J Immunol 1999;29:1684-1691.
17.
Poncini CV, Alba Soto CD, Batalla E, Solana ME, Gonzalez Cappa SM: Trypanosoma cruzi induces regulatory dendritic cells in vitro. Infect Immun 2008;76:2633-2641.
18.
Poncini CV, Gimenez G, Pontillo CA, Alba-Soto CD, de Isola EL, et al: Central role of extracellular signal-regulated kinase and Toll-like receptor 4 in IL-10 production in regulatory dendritic cells induced by Trypanosoma cruzi. Mol Immunol 2010;47:1981-1988.
19.
Alba Soto CD, Mirkin GA, Solana ME, Gonzalez Cappa SM: Trypanosoma cruzi infection modulates in vivo expression of major histocompatibility complex class II molecules on antigen-presenting cells and T-cell stimulatory activity of dendritic cells in a strain-dependent manner. Infect Immun 2003;71:1194-1199.
20.
Gonzalez Cappa SM, Bijovsky AT, Freilij H, Muller L, Katzin AM: Isolation of a Trypanosoma cruzi strain of predominantly slender form in Argentina. Medicina (B Aires) 1981;41:119-120.
21.
Gonzalez Cappa SM, Chiale P, del Prado GE, Katzin AM, de Martini GW, et al: Isolation of a strain of Trypanosoma cruzi from a patient with chronic Chagas cardiomyopathy and its biological characterization. Medicina (B Aires) 1980;41:63-68.
22.
Mirkin GA, Jones M, Sanz OP, Rey R, Sica RE, et al: Experimental Chagas' disease: electrophysiology and cell composition of the neuromyopathic inflammatory lesions in mice infected with a myotropic and a pantropic strain of Trypanosoma cruzi. Clin Immunol Immunopathol 1994;73:69-79.
23.
Risso MG, Garbarino GB, Mocetti E, Campetella O, Gonzalez Cappa SM, et al: Differential expression of a virulence factor, the trans-sialidase, by the main Trypanosoma cruzi phylogenetic lineages. J Infect Dis 2004;189:2250-2259.
24.
Zingales B, Andrade SG, Briones MR, Campbell DA, Chiari E, et al: A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz 2009;104:1051-1054.
25.
Duffy T, Bisio M, Altcheh J, Burgos JM, Diez M, et al: Accurate real-time PCR strategy for monitoring bloodstream parasitic loads in Chagas disease patients. PLoS Negl Trop Dis 2009;3:e419.
26.
Alba Soto CD, Solana ME, Poncini CV, Pino-Martinez AM, Tekiel V, et al: Dendritic cells devoid of IL-10 induce protective immunity against the protozoan parasite Trypanosoma cruzi. Vaccine 2010;28:7407-7413.
27.
Marcusson-Stahl M, Cederbrant K: A flow-cytometric NK-cytotoxicity assay adapted for use in rat repeated dose toxicity studies. Toxicology 2003;193:269-279.
28.
Maleckar JR, Kierszenbaum F: Inhibition of mitogen-induced proliferation of mouse T and B lymphocytes by bloodstream forms of Trypanosoma cruzi. J Immunol 1983;130:908-911.
29.
Scott MJ, Hoth JJ, Turina M, Woods DR, Cheadle WG: Interleukin-10 suppresses natural killer cell but not natural killer T cell activation during bacterial infection. Cytokine 2006;33:79-86.
30.
Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS: Intrahepatic IL-10 maintains NKG2A+Ly49-liver NK cells in a functionally hyporesponsive state. J Immunol 2010;184:2693-2701.
31.
Hiraki S, Ono S, Kinoshita M, Tsujimoto H, Takahata R, et al: Neutralization of IL-10 restores the downregulation of IL-18 receptor on natural killer cells and interferon-gamma production in septic mice, thus leading to an improved survival. Shock 2012;37:177-182.
32.
Alter G, Kavanagh D, Rihn S, Luteijn R, Brooks D, et al: IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection. J Clin Invest 2010;120:1905-1913.
33.
Mandaric S, Walton SM, Rulicke T, Richter K, Girard-Madoux MJ, et al: IL-10 suppression of NK/DC crosstalk leads to poor priming of MCMV-specific CD4 T cells and prolonged MCMV persistence. PLoS Pathog 2012;8:e1002846.
34.
Abrahamsohn IA, Coffman RL: Trypanosoma cruzi: IL-10, TNF, IFN-gamma, and IL-12 regulate innate and acquired immunity to infection. Exp Parasitol 1996;84:231-244.
35.
Gomes JA, Bahia-Oliveira LM, Rocha MO, Martins-Filho OA, Gazzinelli G, et al: Evidence that development of severe cardiomyopathy in human Chagas' disease is due to a Th1-specific immune response. Infect Immun 2003;71:1185-1193.
36.
Penas F, Mirkin GA, Hovsepian E, Cevey A, Caccuri R, et al: PPARgamma ligand treatment inhibits cardiac inflammatory mediators induced by infection with different lethality strains of Trypanosoma cruzi. Biochim Biophys Acta 2013;1832:239-248.
37.
Chaussabel D, Pajak B, Vercruysse V, Bisseye C, Garze V, et al: Alteration of migration and maturation of dendritic cells and T-cell depletion in the course of experimental Trypanosoma cruzi infection. Lab Invest 2003;83:1373-1382.
38.
Vray B, Camby I, Vercruysse V, Mijatovic T, Bovin NV, et al: Up-regulation of galectin-3 and its ligands by Trypanosoma cruzi infection with modulation of adhesion and migration of murine dendritic cells. Glycobiology 2004;14:647-657.
39.
Moretta L, Moretta A: Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 2004;23:255-259.
40.
Tasca S, Tambussi G, Nozza S, Capiluppi B, Zocchi MR, et al: Escape of monocyte-derived dendritic cells of HIV-1 infected individuals from natural killer cell-mediated lysis. AIDS 2003;17:2291-2298.
41.
Mavilio D, Lombardo G, Kinter A, Fogli M, La Sala A, et al: Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection. J Exp Med 2006:203:2339-2350.
42.
Fauriat C, Moretta A, Olive D, Costello RT: Defective killing of dendritic cells by autologous natural killer cells from acute myeloid leukemia patients. Blood 2005;106:2186-2188.
43.
Persson CM, Lambert H, Vutova PP, Dellacasa-Lindberg I, Nederby J, et al: Transmission of Toxoplasma gondii from infected dendritic cells to natural killer cells. Infect Immun 2009;77:970-976.
44.
Maroof A, Beattie L, Zubairi S, Svensson M, Stager S, et al: Post-transcriptional regulation of IL-10 gene expression allows NK cells to express immunoregulatory function. Immunity 2008;29:295-305.
45.
Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, et al: Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe 2009;6:503-512.
46.
Cardillo F, Nomizo A, Postol E, Mengel J: NK1.1 cells are required to control T cell hyperactivity during Trypanosoma cruzi infection. Med Sci Monit 2004;10:BR259-BR267.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.