Dual function for the adaptor MIST in IFN-γ production by NK and CD4⁺NKT cells regulated by the Src kinase Fgr

Natural killer (NK) cells and NKT cells play critical early roles in host defense. Here we show that MIST, an adaptor protein belonging to the SLP-76 family, functions negatively in NK cells but positively in CD4⁺NKT cells. NK-cell receptor-mediated IFN-γ production was enhanced in NK cells, whereas TCR- or NK-cell receptor-mediated cytokine production was reduced in CD4⁺NKT cells from MIST-deficient mice. These opposite effects of MIST paralleled the exclusive expression of the Src family kinase, Fgr, in NK cells between the 2 cell populations. We further demonstrated that interaction of MIST with Fgr, mediated by the C-terminal proline-rich region of MIST and the SH3 domain of Fgr, was required for the suppression of NK-cell receptor-induced IFN-γ production. This functional interdependence of signaling molecules demonstrates a new mechanism by which adaptor proteins can act as molecular switches to control diverse responses in different cell populations.