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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1706-1714
IMMUNOBIOLOGY
Soluble HLA class I molecules induce natural killer cell
apoptosis through the engagement of CD8: evidence for a negative
regulation exerted by members of the inhibitory receptor
superfamily
Grazia Maria Spaggiari,
Paola Contini,
Roberta Carosio,
Marica Arvigo,
Massimo Ghio,
Daniela Oddone,
Alessandra Dondero,
Maria Raffaella Zocchi,
Francesco Puppo,
Francesco Indiveri, and
Alessandro Poggi
From the Laboratory of Immunology, National Cancer
Research Institute, Genoa, Italy; the Laboratory of Clinical
Immunology, Dipartimento di Medicina Interna, Università di
Genova, Genoa, Italy; and the Laboratory of Tumor Immunology,
Scientific Institute San Raffaele, Milan, Italy.
Herein, we show that CD8dull,
CD8intermediate, and CD8bright natural killer
(NK) cell clones can be identified. Triggering of CD8 with its natural ligand(s), represented by soluble HLA class I (sHLA-I), isolated either
from serum of healthy donors or from HLA-I 721.221 lymphoblastoid cell line transfected with HLA-A2, -Cw4, and -Bw46
alleles, or HLA-G1 leads to NK cell apoptosis. The magnitude of this
effect directly correlated with the level of CD8 expression. sHLA-I-induced apoptosis depends on the interaction with CD8, as it
was inhibited by masking this molecule with specific monoclonal antibodies (mAbs). Moreover, sHLA-I or CD8 cross-linking with specific
mAbs elicited intracellular calcium increases, Fas ligand (FasL)
messenger RNA transcription, and FasL secretion, which were needed for
delivering the death signal. Indeed, this apoptosis was inhibited by
preincubation of NK cell clones with Fas or FasL antagonist mAbs,
indicating that the Fas/FasL pathway is involved. Furthermore, members
of the inhibitory receptor superfamily, such as CD94/NKG2 complex or
killer inhibitory receptors, were shown to exert an inhibitory effect
on sHLA-I-mediated apoptosis and secretion of FasL. These findings
suggest that interaction between sHLA-I and CD8 evokes an apoptotic
signal that is down-regulated by inhibitory receptor superfamily that
function as survival receptors in NK cells.
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