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Infect. Immun. doi:10.1128/IAI.00381-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mycobacterium tuberculosis-induced IFN- Production by Natural Killer Cells Requires Cross-Talk with Antigen Presenting Cells Involving Toll-Like Receptors 2 and 4 and Mannose Receptor In Tuberculous Pleurisy

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

^* To whom correspondence should be addressed. Email: msasiain{at}hematologia.anm.edu.ar.

	Abstract

Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis (Mtb) infection. In this study, we find that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early interferon (IFN)- upon Mtb 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-, although a high molecular weight fraction of culture filtrate proteins from Mtb H37Rv and the whole cell lysate also induce its expression. 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- as Mtb does. Antigen presenting cells (APC) and NK cells bind Mtb and, although IL-12 is required it is not sufficient to induce IFN- expression indicating that NK-APC contact takes place. Indeed, MHC-I, adhesion and costimulatory molecules as well as NK receptors regulate IFN- induction. The signaling pathway is partially inhibited by Dexamethasone and sensitive to Ca⁺⁺ flux and Cyclosporin A. Inhibition of p38 and extracellular-regulated kinase mitogen-activated protein kinase pathways reduces the number of IFN-⁺ NK. Phosphorylated-p38 (p-p38) is detected in ex vivo PF-NK cells, and Mtb triggers p-p38 in PF-NK cells at the same time that binding between NK and Mtb has reached the maximum value. Thus, interplay between Mtb and NK/APC triggering IFN- would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile.

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