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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-04-1284.
Submitted April 30, 2002
Accepted July 9, 2002
Soluble HLA class I induces NK cell apoptosis upon the engagement of killer activating HLA class I receptors through FasL/Fas interaction
Grazia Maria Spaggiari, Paola Contini, Alessandra Dondero, Roberta Carosio, Francesco Puppo, Francesco Indiveri, Maria Raffaella Zocchi, and Alessandro Poggi*
Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy
Department of Internal Medicine, University of Genoa, Genoa, Italy
Laboratory of Tumor Immunology, San Raffaele Institute, Milan, Italy
* Corresponding author; email: poggi{at}vega.cba.unige.it.
The engagement of the activating isoforms of C-type Lectin Inhibitory Receptor (CLIR) or Killer Ig-like receptor (KIR) by their natural ligands, represented by soluble HLA-I (sHLA-I) molecules induced programmed cell death of NK cells. Indeed, NK cell apoptosis elicited by either putative HLA-E and HLA-F (sHLA-I non-(A,B,C,G)) or sHLA-I Cw4 or Cw3 from untransfected or Cw4 or Cw3 alleles transfected HLA-A-,B-,C-,G-,E+,F+ 721.221 lymphoblastoid cell line respectively, was blocked by covering the corresponding activating receptor with either anti-CLIR or anti-KIR specific mAbs. After sHLA-I/activating receptor interaction, NK cells produced and released FasL which in turn led to NK cell apoptosis by interacting with Fas at the NK cell surface. Blocking anti-Fas mAb, or anti-FasL mAb, inhibited sHLA-I-mediated apoptosis via activating receptor in NK cell clones. This apoptosis was inhibited by NK cell treatment with cyclosporin A while this drug had no effect on activating receptor-mediated activation of cytolysis. Conversely, concanamycin A, an inhibitor of vacuolar type H+-ATPase of granules, inhibited activating receptor-induced NK cell cytolysis, suggesting that activating receptor-mediated apoptosis and cytolysis can use different intracellular pathways. Furthermore, a large amount of IFN- was detectable in culture supernatant of activating receptor+ NK cells incubated with the appropriate sHLA-I ligand. Again, cyclosporin A, but not concanamycin A, strongly reduced activating receptor-mediated IFN- production. This suggests that activating receptor-induced apoptosis of NK cell could play a role in eliminating potentially harmful NK cell clones and, at the same time, it leads to production of IFN-, an anti-viral cytokine, able to amplify immune responses.
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