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, Alessandro Poggi

Research output: Contribution to journalArticle

Abstract

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 interac tion with CD8, as it was inhibited by masking this molecule with specific monoclonal anti-bodies (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.

Original languageEnglish
Pages (from-to)1706-1714
Number of pages9
JournalBlood
Volume99
Issue number5
DOIs
Publication statusPublished - Mar 1 2002

ASJC Scopus subject areas

  • Hematology

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