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 proliferation in vitro. Their precise role in viva in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation^1-6. The functional receptors for IL-2 and IL-15 consist of a private α-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor β- and γ-chains. The γ-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors⁷. Thus, the γ-chain is called the common γ or γ-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 viva 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 viva T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the γ-c expression. Decreased γ-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.