IFN-gamma production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules.
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-gamma. 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-gamma production was further supported by the finding that cross-linking of CD8 led to release of IFN-gamma at similar levels to those obtained with HLA-I. The sHLA-I-induced IFN-gamma 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-gamma 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-gamma which may play a role in the regulation of innate immune responses in humans.
Laboratory of Immunology, National Institute for Cancer Research (IST), Genoa, Italy.
Grazia Maria
GM
Spaggiari
Paola
P
Contini
Simone
S
Negrini
Alessandra
A
Dondero
Roberta
R
Carosio
Massimo
M
Ghio
Francesco
F
Puppo
Francesco
F
Indiveri
Maria Raffaella
MR
Zocchi
Alessandro
A
Poggi
D016827:CD8 Antigens / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism*
D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D016572:Cyclosporine