IL-2R beta /IL-7R alpha Doubly Deficient Mice Recapitulate the Thymic and Intraepithelial Lymphocyte (IEL) Developmental Defects of gamma c super(-/-) Mice: Roles for Both IL-2 and IL-15 in CD8 alpha alpha IEL Development

IL-7R alpha -chain-deficient (IL-7R alpha super(-/-)) and common gamma chain-deficient ( gamma c super(-/-)) 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 gamma c super(-/-) mice were due to currently defined gamma c-dependent cytokines by cross-breeding IL-7R alpha super(-/-) mice to mice lacking either IL-2, IL-4, or IL-2R beta . IL-2/IL-7R alpha and IL-4/IL-7R alpha double knockout (DKO) mice demonstrated equivalent thymic development to IL-7R alpha super(-/-) mice, whereas IL-2R beta /IL-7R alpha DKO mice, which lack IL-2, IL-7, and IL-15 signaling, displayed thymic T cell defects identical to gamma c super(-/-) mice. Collectively, these data indicate that of the gamma c-dependent cytokines, only IL-7 and IL-15 contribute to the progression and production of thymic T cells. In the IEL, IL-7R alpha super(-/-) mice selectively lack CD8 alpha alpha TCR gamma delta cells, whereas IL-2R beta super(-/-) mice show a significant reduction in all CD8 alpha alpha cells. IL-2 super(-/-) and IL-2/IL-7R alpha DKO mice demonstrated a reduction in CD8 alpha alpha IELs to nearly the same extent as IL-2R beta super(-/-) mice, indicating that IL-2 functions in CD8 alpha alpha IEL development. Moreover, IL-2R beta /IL-7R alpha DKO mice lacked nearly all TCR-bearing IEL, again recapitulating the phenotype of gamma c super(-/-) mice. Thus, these data point to the importance of IL-2, IL-7, and IL-15 as the gamma c-dependent cytokines essential for IEL development.