IFN-γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules
Grazia Maria Spaggiari
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
The first two authors equally contributed to this work.
Search for more papers by this authorSimone Negrini
DIMI, University of Genoa, Genoa, Italy
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Search for more papers by this authorAlessandra Dondero
Laboratory of Tumor Immunology, HSR, Milan, Italy
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Search for more papers by this authorRoberta Carosio
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Search for more papers by this authorMaria Raffaella Zocchi
Laboratory of Tumor Immunology, HSR, Milan, Italy
Search for more papers by this authorCorresponding Author
Alessandro Poggi
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Laboratory of Immunology, National Institute for Cancer Research (IST), C/o CBA, Torre A1, Largo R. Benzi, 10, I-16132 Genoa, Italy Fax: +39-010-354282Search for more papers by this authorGrazia Maria Spaggiari
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
The first two authors equally contributed to this work.
Search for more papers by this authorSimone Negrini
DIMI, University of Genoa, Genoa, Italy
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Search for more papers by this authorAlessandra Dondero
Laboratory of Tumor Immunology, HSR, Milan, Italy
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Search for more papers by this authorRoberta Carosio
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Search for more papers by this authorMaria Raffaella Zocchi
Laboratory of Tumor Immunology, HSR, Milan, Italy
Search for more papers by this authorCorresponding Author
Alessandro Poggi
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy
Laboratory of Immunology, National Institute for Cancer Research (IST), C/o CBA, Torre A1, Largo R. Benzi, 10, I-16132 Genoa, Italy Fax: +39-010-354282Search for more papers by this authorAbstract
The engagement of CD8 on NK cell surface by either surface or soluble HLA class I (sHLA-I) molecules induces synthesis and secretion of IFN-γ. HLA-I-mediated effects were inhibited by the covering of CD8 with specific anti-CD8 monoclonal antibodies, indicating a direct interaction of HLA-I and CD8. That CD8 ligation induces IFN-γ production was further supported by the finding that cross-linking of CD8 led to release of IFN-γ at similar levels to those obtained with HLA-I. The sHLA-I-induced IFN-γ production via CD8 was strongly down-regulated by the engagement of the inhibitory isoforms of either CD94/NKG2 complex by sHLA-I-non-(A,B,C,G) (putative sHLA-E) or CD158b by sHLA-I-Cw3 allele. Ligation of CD8 did not elicit, different from other activating NK cell surface molecules such as CD16 or CD69, triggering of NK cell-mediated cytolysis. Cyclosporin A, but not concanamycin A, an H+-ATPase vacuolar inhibitor which affects perforin and granzyme release, strongly reduced the sHLA-I-mediated CD8-dependent IFN-γ production but did not affect cytolytic activity of NK cells, suggesting that different biochemical pathways are involved. Altogether, these findings indicate that CD8 engagement by sHLA-I activates a cyclosporin A-dependent pathway leading to production and secretion of IFN-γ which may play a role in the regulation of innate immune responses in humans.
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