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Pertussis Toxin (PTX) B Subunit and the Nontoxic PTX Mutant PT9K/129G Inhibit Tat-Induced TGF- Production by NK Cells and TGF--Mediated NK Cell Apoptosis ¹

M. Raffaella Zocchi^*, Paola Contini, Massimo Alfano and Alessandro Poggi^2,

^* Laboratory of Tumor Immunology and AIDS Immunopathogenesis Unit, Department of Immunology and Infectious Diseases, Scientific Institute San Raffaele, Milan, Italy; and Department of Internal Medicine, Department of Internal Medicine, University of Genoa, and Laboratory of Experimental Oncology D, National Institute for Cancer Research, Genoa, Italy

We show that the pertussis toxin B oligomer (PTX-B), and the PTX mutant PT9K/129G, which is safely administered in vivo, inhibit both transcription and secretion of TGF- elicited by HIV-1 Tat in NK cells. Tat-induced TGF- mRNA synthesis is also blocked by the ERK1 inhibitor PD98059, suggesting that ERK1 is needed for TGF- production. Moreover, Tat strongly activates the c-Jun component of the multimolecular complex AP-1, whereas TGF- triggers c-Fos and c-Jun. Of note, treatment of NK cells with PTX-B or PT9K/129G inhibits Tat- and TGF--induced activation of AP-1. TGF- enhances starvation-induced NK cell apoptosis, significantly reduces transcription of the antiapoptotic protein Bcl-2, and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF--mediated effects are prevented by PTX-B or PT9K/129G through a PI3K-dependent mechanism, as demonstrated by use of the specific PI3K inhibitor, LY294002. Finally, PTX-B and PT9K/129G up-regulate Bcl-x_L, the isoform of Bcl-x that protects cells from starvation-induced apoptosis. It is of note that in NK cells from patients with early HIV-1 infection, mRNA expression of Bcl-2 and Bcl-x_L was consistently lower than that in healthy donors; interestingly, TGF- and Tat were detected in the sera of these patients. Together, these data suggest that Tat-induced TGF- production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.

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