The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans; in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID; and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. During the past year, the group reported the successful gene-therapeutic reconstitution of the defect in gc-knockout mice, establishing proof of principal in mice as a step towards the human gene therapy for XSCID. Interestingly, the correction could occur with human gc, indicating the ability of human gc to functional cooperate with murine cytokines and the other receptor components of these murine cytokines. The group also reported that a negative regulator of cytokine signaling, CIS (cytokine-inducible SH2 containing protein; also called CIS1) associates with IL-2Rb and inhibits IL-2 signaling and advanced its work on a related protein, denoted JAB/SOCS1/SSI-1. Work on the identification of IL-2-inducible genes continued. Finally, the group reported the cDNA cloning of a novel type I cytokine receptor protein which was demonstrated to be the receptor for thymic stromal lymphopoietin (TSLP). Interestingly, like IL-7, TSLP is derived from stroma. Its receptor consists of the IL-7Ra + TSLPR, whereas IL-7 signals through a receptor comprising IL-7Ra + gc. These findings help to explain the greater defect in IL-7Ra-deficient mice (which thereby lack signaling via IL-7 and TSLP) than in IL-7-deficient mice (in which only IL-7 signaling is defective). Overall, these studies help to aspects of signaling by IL-2 and related cytokines. These findings have relevance to immunodeficiency and the control of T-cell growth.
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