Soluble HLA class I induces NK cell apoptosis upon the engagement of killer-activating HLA class I receptors through FasL-Fas interaction

被引:93
作者
Spaggiari, GM
Contini, P
Dondero, A
Carosio, R
Puppo, F
Indiveri, F
Zocchi, MR
Poggi, A
机构
[1] CBA, IST, Natl Inst Canc Res, Immunol Lab, I-16132 Genoa, Italy
[2] Univ Genoa, DIMI, I-16126 Genoa, Italy
[3] Ist Sci San Raffaele, Lab Tumor Immunol, Milan, Italy
关键词
D O I
10.1182/blood-2002-04-1284
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 natural killer (NK) cells. Indeed, NK cell apoptosis elicited by either putative HLA-E and HLA-F (sHLA-I non-A, -B, -C, and -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 monoclonal antibodies (mAbs). After sHLA-I-activating receptor interaction, INK cells produced and released Fas ligand (FasL), which in turn led to INK cell apoptosis by interacting with Fas at the INK 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 INK cell treatment with cyclosporin A, whereas this drug had no effect on activating receptor-mediated activation of cytolysis. Conversely, concanamycin A, an inhibitor of vacuolar type H+-adenosine triphosphatase (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 interferon-gamma (IFN-gamma) was detectable in culture supernatant of activating receptor(+) INK cells incubated with the appropriate sHLA-I ligand. Again, cyclosporin A, but not concanamycin A, strongly reduced activating receptor-mediated IFN-gamma production. This suggests that activating receptor-induced apoptosis of NK cells could play a role in eliminating potentially harmful NK cell clones and, at the same time, it leads to production of IFN-gamma, an antiviral cytokine able to amplify immune responses. (C) 2002 by The American Society of Hematology.
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页码:4098 / 4107
页数:10
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