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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-04-1284.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4098-4107
IMMUNOBIOLOGY
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
From the Laboratory of Immunology, National Institute
for Cancer Research (IST), Genoa; DIMI, University of Genoa; and
Laboratory of Tumor Immunology, Istituto Scientifico San Raffaele,
Milan, Italy.
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, NK
cells produced and released Fas ligand (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, 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- (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 cells
could play a role in eliminating potentially harmful NK cell clones
and, at the same time, it leads to production of IFN-, an antiviral
cytokine able to amplify immune responses.
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