The role of IL-15 and survival signals in natural killer cell development, maintenance, and activation

IL-15 and IL-15Rα are essential for the generation and maintenance of natural killer cells, and play a supporting role in their activation. Several groups have shown that the effects of IL-15 in the periphery are mediated by survival of NK cells through upregulation of bcl-2 family members. To determine if the IL-15Rα requirements for the development of NK cells are also mediated by survival via bcl-2 upregulation, we crossed transgenic mice over expressing bcl-2 under the H2Kb promoter with IL-15Rα deficient mice. In the resulting mice NK cell development was not restored indicating that differentiation signals consisting of more than just survival are necessary for NK cell lineage progression. In contrast, adoptive transfer experiments have shown that the peripheral maintenance of NK cells is dependent on IL-15Rα expression in the environment, and their survival can be enhanced through over-expression of bcl-2. Through the use of bone marrow chimeras, we have also determined that the expression of IL-15 and IL-15Rα by NK cells is not required as long as cells in their environment express these factors; however, the self-autonomous expression of IL-2/15Rβ is required. Utilizing these bone marrow chimeras, we generated mature NK cells that lack IL-15Rα expression and were able to activate them during MCMV infection; however, the absence of this receptor created a modest decrease in their proliferation. In addition, over-expression of bcl-2 on NK cells during MCMV infection increased their expansion and substantially delayed their contraction phase. Finally, I evaluated novel strategies to dissect the role of cytokines in the bone marrow versus peripheral tissues. ^