IL-2Rbeta/IL-7Ralpha doubly deficient mice recapitulate the thymic and intraepithelial lymphocyte (IEL) developmental defects of gammac-/- mice: roles for both IL-2 and IL-15 in CD8alphaalpha IEL development.

IL-7Ralpha-chain-deficient (IL-7Ralpha-/-) and common gamma chain-deficient (gammac-/-) mice both exhibit abnormal thymic and intestinal intraepithelial lymphocyte (IEL) development, but the developmental inhibition is not equivalent. In this report, we assessed whether the defects in T cell development associated with gammac-/- mice were due to currently defined gammac-dependent cytokines by cross-breeding IL-7Ralpha-/- mice to mice lacking either IL-2, IL-4, or IL-2Rbeta. IL-2/IL-7Ralpha and IL-4/IL-7Ralpha double knockout (DKO) mice demonstrated equivalent thymic development to IL-7Ralpha-/- mice, whereas IL-2Rbeta/IL-7Ralpha DKO mice, which lack IL-2, IL-7, and IL-15 signaling, displayed thymic T cell defects identical to gammac-/- mice. Collectively, these data indicate that of the gammac-dependent cytokines, only IL-7 and IL-15 contribute to the progression and production of thymic T cells. In the IEL, IL-7Ralpha-/- mice selectively lack CD8alphaalpha TCRgammadelta cells, whereas IL-2Rbeta-/- mice show a significant reduction in all CD8alphaalpha cells. IL-2-/- and IL-2/IL-7Ralpha DKO mice demonstrated a reduction in CD8alphaalpha IELs to nearly the same extent as IL-2Rbeta-/- mice, indicating that IL-2 functions in CD8alphaalpha IEL development. Moreover, IL-2Rbeta/IL-7Ralpha DKO mice lacked nearly all TCR-bearing IEL, again recapitulating the phenotype of gammac-/- mice. Thus, these data point to the importance of IL-2, IL-7, and IL-15 as the gammac-dependent cytokines essential for IEL development.