IL-2Rβ/IL-7Rα doubly deficient mice recapitulate the thymic and intraepithelial lymphocyte (IEL) developmental defects of γc-/- mice:: Roles for both IL-2 and IL-15 in CD8αα IEL development

IL-7R alpha-chain-deficient (IL-7R alpha(-/-)) and common gamma chain-deficient (gamma c(-/-)) 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(-/-) mice were due to currently defined gamma c-dependent cytokines by cross-breeding IL-7R alpha(-/-) 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(-/-) 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(-/-) 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(-/-) mice selectively lack CD8 alpha alpha TCR gamma delta cells, whereas IL-2R beta(-/-) mice show a significant reduction in all CD8 alpha alpha cells. IL-2(-/-) 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(-/-) 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(-/-) mice. Thus, these data point to the importance of IL-2, IL-7, and as the gamma c-dependent cytokines essential for IEL development.