IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1A-mediated down-regulation of NK cell activation.
IL-12, in contrast to IL-2, strongly up-regulated the expression of the NKRP1A lectin molecule on human NK cells. This effect appeared to be specific for NKRP1A as the expression of other functional NK cell surface molecules such as CD16 and different killer inhibitory receptors (KIR) including CD158a and CD158b, p70 and p140 were not affected by culture in IL-12. In addition, we found that polyclonal or clonal NK cell populations derived in the presence of IL-2 displayed an increased expression of NKRP1A after culture in IL-12. The IL-12-induced NKRP1A expression was time and dose dependent, reaching a maximum by 7 days of culture in the presence of 2 ng/ml IL-12 and it was inhibited by the addition of anti-IL-12 monoclonal antibody. The IL-12-dependent NKRP1A up-regulation was abrogated by the incubation of NK cells with actinomycin D, thus suggesting that IL-12 induces de novo transcription of NKRP1A mRNA. Functional analysis revealed that the engagement of the NKRP1A molecule in IL-12- but not in IL-2-cultured NK cells leads to a strong inhibition of the cytolytic activity induced by cross-linking of CD16 or p46, a recently described NK cell-specific triggering surface molecule. Our findings suggest that IL-12 up-regulates the expression of NKRP1A which, in turn, can regulate NK cell activation induced via different triggering pathways. This would imply that NKRP1A-mediated functions may be regulatd by the cytokine microenvironment that NK cells may encounter at inflammatory sites.
Poggi
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Istituto Nazionale per la Ricerca sul Cancro (IST), and Centro di Biotecnologie Avanzate, Genova, Italy.
Costa
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Tomasello
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Moretta
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D000954:Antigens, Surface / Q000096:biosynthesis*; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055627:Natural Cytotoxicity Triggering Receptor 1; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*
D000954:Antigens, Surface; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; C112260:NCR1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055627:Natural Cytotoxicity Triggering Receptor 1; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D018664:Interleukin-12