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Infection and Immunity, November 2007, p. 5325-5337, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00381-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mycobacterium tuberculosis-Induced Gamma Interferon Production by Natural Killer Cells Requires Cross Talk with Antigen-Presenting Cells Involving Toll-Like Receptors 2 and 4 and the Mannose Receptor in Tuberculous Pleurisy{triangledown}

Pablo Schierloh,1 Noemí Yokobori,1 Mercedes Alemán,1 Verónica Landoni,1 Laura Geffner,1 Rosa M. Musella,2 Jorge Castagnino,2 Matias Baldini,2 Eduardo Abbate,2 Silvia S. de la Barrera,1 and María C. Sasiain1*

Departamento de Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina,1 División de Tisioneumonología, Hospital F. J. Muñiz, Buenos Aires, Argentina2

Received 13 March 2007/ Returned for modification 3 May 2007/ Accepted 3 August 2007

Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis infection. In this study, we found that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early gamma interferon (IFN-{gamma}) upon M. tuberculosis stimulation, leading us to investigate the mechanisms and molecules involved in this process. We show that the whole bacterium is the best inducer of IFN-{gamma}, although a high-molecular-weight fraction of culture filtrate proteins from M. tuberculosis H37Rv and the whole-cell lysate also induce its expression. The mannose receptor seems to mediate the inhibitory effect of mannosylated lipoarabinomannan, and Toll-like receptor 2 and 4 agonists activate NK cells but do not induce IFN-{gamma} like M. tuberculosis does. Antigen-presenting cells (APC) and NK cells bind M. tuberculosis, and although interleukin-12 is required, it is not sufficient to induce IFN-{gamma} expression, indicating that NK cell-APC contact takes place. Indeed, major histocompatibility complex class I, adhesion, and costimulatory molecules as well as NK receptors regulate IFN-{gamma} induction. The signaling pathway is partially inhibited by dexamethasone and sensitive to Ca2+ flux and cyclosporine. Inhibition of p38 and extracellular-regulated kinase mitogen-activated protein kinase pathways reduces the number of IFN-{gamma}+ NK cells. Phosphorylated p38 (p-p38) is detected in ex vivo PF-NK cells, and M. tuberculosis triggers p-p38 in PF-NK cells at the same time that binding between NK and M. tuberculosis reaches its maximum value. Thus, interplay between M. tuberculosis and NK cells/APC triggering IFN-{gamma} would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile.

* Corresponding author. Mailing address: Instituto de Investigaciones Hematológicas, Immunology Department, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina. Phone: 5411-48055695. Fax: 5411-48039475. E-mail: msasiain{at}hematologia.anm.edu.ar

{triangledown} Published ahead of print on 20 August 2007.

Editor: J. L. Flynn

Infection and Immunity, November 2007, p. 5325-5337, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00381-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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