The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID.

Interleukin 2 (IL-2), a T cell-derived cytokine, targets a variety of cells to induce their growth, differentiation, and functional activation. IL-2 inserts signals into the cells through IL-2 receptors expressed on cell surfaces to induce such actions. In humans, the functional IL-2 receptor consists of the subunit complexes of the alpha, beta and gamma chains, or the beta and gamma chains. The third component, the gamma chain, of IL-2 receptor plays a pivotal role in formation of the full-fledged IL-2 receptor, together with the beta chain, the gamma chain participates in increasing the IL-2 binding affinity and intracellular signal transduction. Moreover, the cytokine receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 utilize the same gamma chain as an essential subunit. Interestingly, mutations of the gamma chain gene cause human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or profound T cell defect. Among the cytokines sharing the gamma chain, at least IL-7 is essentially involved in early T cell development in the mouse organ culture system. The molecular identification of the gamma chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. To investigate the mechanism of XSCID and development of gene therapy for XSCID, knockout mice for the gamma chain gene were produced that showed similar but not exactly the same phenotypes as human XSCID.