The interleukin 7 receptor (IL-7R) plays a crucial role in early B-and T-cell development. It consists of a unique a chain and a common y chain [IL-2 receptor y chain (IL-2Ry)]. Gene inactivation of IL-7, IL-7R, and IL-2Ry resulted in severe impairment of B and T lymphopoiesis in mice. In addition, IL-2Ry-deficient mice lack yS T cells in the skin and have the impaired development of natural killer (NK) cells and intraepithelial lymphocytes. To explore the role of IL-7/IL-7R system in yS T-and NK-cell development, we have generated and analyzed IL-7R-deficient mice. y6 T cells were absent from skin, gut, liver, and spleen in the deficient mice. In contrast, c43 T and B cells were detected in reduced, but certain, numbers, and NK cells developed normally. The y6 T-cell development in fetal and adult thymus was also completely blocked. These results clearly demonstrate that the signal from IL-7R is indispensable for y6 T-cell development in both thymic and extrathymic pathways. On the contrary, it is suggested that NK-cell development requires cytokine(s) other than IL-7.Interleukin 7 (IL-7) is a growth factor for early B-and T-cell precursors. It was first characterized by its ability to support the growth of B-cell precursors. Subsequently, it has been shown to support survival and growth of early thymocytes and promote rearrangement of T-cell receptor (TCR) ,B and -y chains in fetal thymus and fetal liver cultures (1, 2). In vivo administration of neutralizing antibodies to IL-7 and IL-7 receptor (IL-7R) resulted in the inhibition of both B and T lymphopoiesis (3, 4). IL-7R consists of two polypeptides: a unique a chain (IL-7Ra) and a common -y chain (IL-2R 'y chain, IL-2R-y) (5, 6). IL-7R shares the IL-2R-y with the receptors for IL-2, IL-4, IL-9, and IL-15 (7 and V-y4 but not of V-y3 or V-y5 genes and sustained expression of RAG-1 and RAG-2 genes (1, 2). Collectively, these results strongly suggest that IL-7 may be also involved in the development and the maintenance of 'y6 T cells in the thymus and the periphery. Gene inactivation studies have been carried out to elucidate the in vivo function of various cytokines and their receptors. In IL-2R-y-deficient mice, numbers of T, B, and natural killer (NK) cells are reduced (15,16). In addition, DETCs are absent from the skin and the development of IELs is severely diminished. In contrast, mice deficient for IL-2, IL-4, or both cytokines have normal numbers of mature T and B cells (17, 18). On the other hand, in both IL-7-and IL-7R-deficient mice, the numbers of lymphocytes are reduced (19,20), suggesting that the impairment of T and B lymphopoiesis in IL-2Ry-deficient mice is caused by depletion of the signal by IL-7. However, studies have not been reported on the development of y8 T and NK cells in IL-7R-deficient mice.To elucidate the role of IL-7/IL-7R system in y8 T-cell development, we have generated and analyzed IL-7R-deficient mice. yS T cells were absent from these mice, while decreased, but certain, numbers of mature af3 T cells were detected. ...