Development and Maintenance of NK Cells Dendritic Cells Support the In Vivo

IL-15 is a key component that regulates the development and homeostasis of NK cells and is delivered through a mechanism termed trans-presentation. During development, multiple events must proceed to generate a functional mature population of NK cells that are vital for tumor and viral immunity. Nevertheless, how IL-15 regulates these various events and more importantly what cells provide IL-15 to NK cells to drive these events is unclear. It is known dendritic cells (DC) can activate NK cells via IL-15 trans-presentation; however, the ability of DC to use IL-15 trans-presentation to promote the development and homeostatic maintenance of NK cell has not been established. In this current study, we show that IL-15 trans-presentation solely by CD11c ؉ cells assists the in vivo development and maintenance of NK cells. More specifically, DC-mediated IL-15 trans-presentation drove the differentiation of NK cells, which included the up-regulation of the activating and inhibitory Ly49 receptors. Although these cells did not harbor a mature CD11b high phenotype, they were capable of degranulating and producing IFN-␥ upon stimulation similar to wild-type NK cells. In addition, DC facilitated the survival of mature NK cells via IL-15 trans-presentation in the periphery. Thus, an additional role for NK-DC interactions has been identified whereby DC support the developmental and homeostatic niche of NK cells. T he functional plasticity of NK cells in tumor and viral immunity has revealed their significance as instrumental lymphocytes in the innate immune system (1–3). Thus, NK cell development is of great importance for host immunopro-tection. Several groups have deciphered the multistage events that murine NK cells undergo to become functional mature lympho-cytes (4, 5). The earliest stage of NK cell commitment are noted as NK precursors (NKp), 4 which are negative for known murine NK markers, such as NKR-P1C (NK1.1) and Ly49 receptors, but express IL-15R␤ (CD122) (6). Transition from NKp to immature NK cells is marked by the expression of NK1.1 and CD94/NKG2, followed by the stochastic expression of various activating and inhibitory Ly49 receptors. Mature NK cells are distinguished from immature cells by the expression of CD49b (DX5) and by the capacity to kill and produce proinflammatory cytokines (4, 7). These functional attributes are enhanced with the up-regulation of CD11b and CD43. Within this differentiation process, there exist other developmental events such as proliferation and NK cell " licensing " (also referred to as " disarming ") (8, 9). Licensing is the process that …