Natural killer (NK) cell development is thought to occur in the bone marrow. Here we identify the transcription factor GATA-3 and CD127 (IL-7R alpha) as molecular markers of a pathway of mouse NK cell development that originates in the thymus. Thymus-derived CD127+ NK cells repopulated peripheral lymphoid organs, and their homeostasis was strictly dependent on GATA-3 and interleukin 7. The CD127+ NK cells had a distinct phenotype (CD11b(lo) CD16- CD69(hi) Ly49(lo)) and unusual functional attributes, including reduced cytotoxicity but considerable cytokine production. Those characteristics are reminiscent of human CD56(hi) CD16- NK cells, which we found expressed CD127 and had more GATA-3 expression than human CD56+ CD16+ NK cells. We propose that bone marrow and thymic NK cell pathways generate distinct mouse NK cells with properties similar to those of the two human CD56 NK cell subsets.

The interleukin 2 receptor y chain (IL-2R'y) is a component of the receptors for IL-2, IL-4, IL-7, and IL-15. Mutations in IL-2Ry in man appear responsible for the X chromosome-linked immunodeficiency SCIDX1, characterized by a defect in T-cell and natural killer (NK)-cell differentiation with the presence of poorly functioning B cells. To explore at which level IL-2Ry affects lymphoid development in vivo, we have analyzed mice derived from embryonic stem (ES) cells with mutant IL-2Ry loci generated by Cre/loxPmediated recombination. In the peripheral blood of chimeric animals, lymphoid cells derived from IL-2Ry-ES cells were not detected, although control ES cells carrying an IL-2R'y gene with embedded loxP sites gave rise to T-, B-, and NK-cell lineages. Germline IL-2Ry-deficient male animals, however, developed some mature splenic B and T cells, although the absolute number of lymphocytes was almost 10-fold reduced. In contrast, there was a complete disappearance of NK cells (over 350-fold reduction). Development of gut-associated intraepithelial lymphocytes was also severely diminished, and Peyer's patches were not detected. In vitro mitogenic responses of thymocytes, IL-4-directed immunoglobulin class switch of splenocytes, and NK activity were defective. Thus, IL-2Ry facilitates mainstream B-and T-cell generation and function and also appears to be essential for NK-cell development.Lymphoid development results from the expansion and differentiation of committed precursor cells under the influence of the bone marrow, thymic, and gut microenvironments, which requires both stem cell-stromal cell contact and interactions between soluble cytokines and their receptors (1, 2). The interleukin 2 receptor y chain (IL-2Ry), initially identified as an effector component of the IL-2R (3), figures prominantly in lymphopoiesis, through its participation in the receptors for IL-2, IL-4, IL-7, and IL-15 (4-8). Severe combined immunodeficiency Xl (SCIDX1), an X chromosomelinked immunodeficiency characterized by a severe block in T-cell and NK-cell differentiation with the presence of normal or elevated numbers of poorly functioning B cells (9, 10), is associated with mutations in IL-2Ry (11). Still, the level at which IL-2Ry mutations disrupt normal cytokine/receptor function and cause SCIDX1 is not known.A variety of lymphokines play a role in the early stages of lymphoid development. In mice, in vivo blockade of the IL-7/IL-7R system with antibodies results in a complete block in B-cell generation and a substantial decrease in T lymphopoiesis (12, 13). In contrast, mice deficient for IL-2, IL-4, or both lymphokines have normal numbers of mature B and T cells (14-16). Therefore the phenotype in human SCIDX1 (near absence of T cells, elevated proportions of B cells) cannot be easily explained by defects in the IL-2, IL-4, or IL-7 receptor systems, without a species-specific difference in receptor function. In addition, the use of IL-2Ry in additional cytokine receptors (such as IL-15R and perhaps others) and the r...