There are two IL-15 isoforms and eight isoforms for the IL-15Ralpha chain whose biological role is poorly understood. Here, we have analysed the intracellular trafficking of IL-15 and IL-15Ralpha and tried to shed some light on their function(s). In IL-15/GFP CHO transfectants both IL-15 isoforms show nuclear localization. Two melanoma cell lines (MELP and MELREO) spontaneously expressing the IL-15 isoforms, display different intracellular trafficking of the IL-15/IL-15Ralpha complex. In MELP cells only IL-15Ralpha is detected inside the nucleus, whereas IL-15 and IL-15Ralpha assemble at the cell surface and are internalized. Moreover, the transducing molecule TRAF2 co-immunoprecipitates with IL-15Ralpha and may be deflected to TNFRI using anti-IL-15 blocking mAbs and TNF-alpha. By contrast, MELREO cells display IL-15Ralpha and IL-15 nuclear localization but only a partial co-localization of these molecules on the cell surface. In these cells, TRAF2 is strongly associated with IL-15Ralpha and cannot be deflected by any treatment. Since TRAF2 activates the transcription factor NF-kappaB, IL-15 through IL-15Ralpha, could have a role in the control of this pathway. Indeed, anti-IL-15 MaB inhibit the constitutive nuclear localization of NFkappaB and the phosphorylation of its inhibitor Ikappa-Balpha. Thus, IL-15Ralpha controls NF-kappaB activation, however differences in the intracellular trafficking of the IL-15 and/or IL-15Ralpha suggest a different biological role for this complex in MELP versus MELREO cells.