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The Journal of Immunology, 1999, 163: 5906-5912.
Copyright © 1999 by The American Association of Immunologists

IL-2Rß/IL-7R{alpha} Doubly Deficient Mice Recapitulate the Thymic and Intraepithelial Lymphocyte (IEL) Developmental Defects of {gamma}c-/- Mice: Roles for Both IL-2 and IL-15 in CD8{alpha}{alpha} IEL Development1

Brian O. Porter and Thomas R. Malek2

Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101

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-2Rß. 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-2Rß/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-2Rß-/- 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-2Rß-/- mice, indicating that IL-2 functions in CD8{alpha}{alpha} IEL development. Moreover, IL-2Rß/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 IL-15 as the {gamma}c-dependent cytokines essential for IEL development.




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