DIFFERENTIAL TRANSCRIPTIONAL REGULATION OF CD161 AND A NOVEL GENE, 197 15A, BY IL-2, IL-15, AND IL-12 IN NK AND T-CELLS/

Cytokine-mediated enhancement of spontaneous cytotoxicity depends, at least in part, on modulation of the expression of surface molecules re sponsible for recognition of target cell structures and triggering or inhibition of the cytotoxic machinery. We previously demonstrated that expression of transcription factors (e.g., Egr-1, JunB, and c-Fos) is differentially regulated by IL-2 and IL-12. Here we show that express ion of CD161/NKR-P1A, a molecule involved in triggering cytotoxicity, is specifically upregulated by IL-12. CD161 transcription, mRNA accumu lation, and surface expression are increased by IL-12. Other cytokines sharing the IL-2R beta- and/or common gamma-chains (i.e., IL-15, IL-4 , and IL-7) do not mediate these effects. In an effort to analyze the mechanisms by which IL-2,IL-12, and IL-15 differentially regulate gene transcription, we have isolated a novel gene, 197/15a, the expression of which in NK and T cells is down-regulated by IL-2 and IL-15, up-re gulated by IL-12, and not affected by IL-4 and IL-7. IL-2 and IL-15 ac t, at least in part, repressing 197/15a transcription; their effect on 197/I5a mRNA accumulation is partially independent of novel protein s ynthesis, likely not mediated by JunB, Bcl-2, or Bar, and requires the activity of rapamycin-sensitive molecule(s). The observation that IL- 2 and IL-12 differentially modulate CD161 expression suggests the exis tence of cytokine-specific mechanisms of modulation of spontaneous cyt otoxicity based on the regulation of expression of surface molecules i nvolved in target cell recognition and/or triggering of the cytolytic machinery.