IL-15 and IL-2: a matter of life and death for T cells in vivo

Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferat ion in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regu late distinct aspects of T-cell activation(1-6). The functional receptors f or IL-2 and IL-15 consist of a private ex-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma -ch ains. The gamma -chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors(7). Thus, the gamma -chain is called the common gamma o r gamma -c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both(7,8), We hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunit s, we demonstrate that IL-15 is a critical growth factor in initiating T ce ll divisions in vivo, whereas IL-2 limits continued T-cell expansion via do wnregulation of the gamma -c expression. Decreased gamma -c expression on c ycling T cells reduced sustained Bcl-2 expression and rendered cells suscep tible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.