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

Abstract

AbstractIL-7Rα-chain-deficient (IL-7Rα−/−) and common γ chain-deficient (γc−/−) 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 γc−/− mice were due to currently defined γc-dependent cytokines by cross-breeding IL-7Rα−/− mice to mice lacking either IL-2, IL-4, or IL-2Rβ. IL-2/IL-7Rα and IL-4/IL-7Rα double knockout (DKO) mice demonstrated equivalent thymic development to IL-7Rα−/− mice, whereas IL-2Rβ/IL-7Rα DKO mice, which lack IL-2, IL-7, and IL-15 signaling, displayed thymic T cell defects identical to γc−/− mice. Collectively, these data indicate that of the γc-dependent cytokines, only IL-7 and IL-15 contribute to the progression and production of thymic T cells. In the IEL, IL-7Rα−/− mice selectively lack CD8αα TCRγδ cells, whereas IL-2Rβ−/− mice show a significant reduction in all CD8αα cells. IL-2−/− and IL-2/IL-7Rα DKO mice demonstrated a reduction in CD8αα IELs to nearly the same extent as IL-2Rβ−/− mice, indicating that IL-2 functions in CD8αα IEL development. Moreover, IL-2Rβ/IL-7Rα DKO mice lacked nearly all TCR-bearing IEL, again recapitulating the phenotype of γc−/− mice. Thus, these data point to the importance of IL-2, IL-7, and IL-15 as the γc-dependent cytokines essential for IEL development.