Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-gamma production.
Activation of NK cells is triggered by multiple receptors. We demonstrate here that SLP-76 is required for CD16- and NKG2D-mediated NK cell cytotoxicity, while MIST negatively regulates these responses in an SLP-76-dependent manner. Exceptionally, MIST acts as a positive regulator of cytotoxicity against YAC-1 cells, although SLP-76 plays a more key role. SLP-76 acts as a dominant positive regulator for both NKG2D-mediated and YAC-1 cell-triggered IFN-gamma production. Although NKG2D-mediated IFN-gamma production depends on phospholipase C (PLC) gamma 2, YAC-1 cell-triggered IFN-gamma production is PLC gamma 2- and Syk/ZAP-70 independent and nuclear factor-kappa B mediated. SLP-76 is required for this process in the presence of MIST but is dispensable in the absence of MIST. Thus, YAC-1 cell-triggered NKG2D-independent IFN-gamma production appears to be regulated by SLP-76-dependent and -independent pathways, in which the latter is negatively regulated by MIST. Taken together, these results suggest that SLP-76 and MIST distinctly but interactively regulate NK cell cytotoxicity and IFN-gamma production.
Hidano
Shinya
S
Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
Sasanuma
Hiroki
H
Ohshima
Keiko
K
Seino
Ken-ichiro
K
Kumar
Lalit
L
Hayashi
Katsuhiko
K
Hikida
Masaki
M
Kurosaki
Tomohiro
T
Taniguchi
Masaru
M
Geha
Raif S
RS
Kitamura
Daisuke
D
Goitsuka
Ryo
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C488191:Clnk protein, mouse; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D007371:Interferon-gamma