t has long been recognized that human X-linked severe combined immunodeficiency disease (X-SCID) is an inherited and usually fatal syndrome characterized by impaired T-cell development 1,2 . Affected patients lack T cells, but have a near normal number of B cells that primarily secrete IgM. The B-cell dysfunction is partially accounted for by impaired T helper cell function. However, a non-random pattern of X-chromosome inactivation has been seen in T cells, natural killer (NK) cells and B cells in obligate carriers of this disease, implicating the common ␥ chain (␥c) of cytokine receptors in the development/maturation of each of these lymphoid cell populations 3,4 . Shortly after cloning the ␥c of the interleukin-2-receptor (IL-2R), chromosomal mapping of this gene localized it to Xq13, closely linked to the well-known X-SCID locus 5,6 .
Patients with X-SCID were shown to possess mutations in the ␥c, establishing defects in this gene as the cause of X-SCID. However, based on the results obtained with knockout mice, deficiency in IL-2-IL-2R signaling seemed to be an unlikely explanation for the abnormalities associated with X-SCID. The subsequent realization that the IL-2R␥ subunit is also a component of the receptors for IL-4, IL-7, IL-9 and IL-15 indicated that impairment of ␥c could lead to defects in the function of many cytokines, providing a plausible explanation for the pathophysiology of this disease. A more precise understanding of the role of individual ␥c-dependent cytokines in T-cell development, as discussed below, has emerged from the phenotypic characterization of mice with a blockade in an individual cytokine or cytokine receptor subunit.
␥c in lymphoid cell development Mice versus humans
Substantial impairment in the development of all lymphoid lineage cells is found in ␥c-deficient mice, whereas the development of erythromyeloid lineages proceeds normally 7,8 . Mice deficient in the ␥c-associated tyrosine kinase (JAK3) exhibit the same types of abnormalities in lymphocyte development as those seen in ␥c-deficient mice [9] , suggesting an important role for this intracellular signaling molecule during lymphoid development. In Box 1 the phenotype of ␥c-deficient mice is compared with that of human X-SCID patients and mice treated with monoclonal antibodies (mAbs) to ␥c. Each case shows impaired lymphoid cell development, although there are some notable differences.
Unlike X-SCID patients, a few T cells do develop in ␥c-deficient mice, as young adult mice possess ~1-3% of the normal number of thymocytes. Thus, there is not an absolute requirement for ␥c in the 30