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

• Published in: Blood Vol. 99; no. 5; pp. 1706 - 1714
• Main Authors: Spaggiari, Grazia Maria, Contini, Paola, Carosio, Roberta, Arvigo, Marica, Ghio, Massimo, Oddone, Daniela, Dondero, Alessandra, Zocchi, Maria Raffaella, Puppo, Francesco, Indiveri, Francesco, Poggi, Alessandro
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.03.2002; The Americain Society of Hematology
• Subjects: Apoptosis - drug effects; Biological and medical sciences; Calcium Signaling - drug effects; CD8 Antigens - analysis; CD8 Antigens - metabolism; Down-Regulation; Fas Ligand Protein; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Histocompatibility Antigens Class I - pharmacology; Humans; Immunobiology; Killer Cells, Natural - cytology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Ligands; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Modulation of the immune response (stimulation, suppression); Protein Binding; Receptors, Immunologic - physiology; Receptors, KIR; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; Solubility; Natural killer cell; Human; Fas ligand; HLA-System; T cell receptor; Fas antigen; Major histocompatibility system; T-Lymphocyte; Immune regulation; Class I histocompatibility antigen; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.5.1706

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.