IL-2 Family Cytokines and their Receptors--Biology of the IL-7/TSLP Systems

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The 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, we 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. We reported 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. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. In prior work, we also had identified and studied thymic stromal lymphopoeitin (TSLP), whose binding protein, TSLPR, is most related to gc, and we showed that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the function of TSLP and IL-7 are distinctive. We showed that TSLP promotes CD4 T cell development whereas IL-7 and IL-15, which also share gc, favor CD8 T cell development, and that TSLP plays a critical role in the develop of allergic asthma in a mouse model system. In collaboration with the Lodish lab, we previously reported the cloning of TSLPR and demonstrated that TSLP, counter to the sense of the literature, exerted some of its major actions via CD4+ T cells in both humans and mice. In the past year, we showed that TSLP and IL-7, which share IL-7Ra as a receptor component, both drive the development of regulatory T cells. Interestingly IL-7Ra is essential for the development of these cells but mice deficient in either IL-7 or TSLPR developed relatively normal numbers of these cells. Thus, these two cytokines appear to exhibit partially overlapping actions for IL-7 and TSLP. We also showed that TSLP is not sufficient to mediate the thymopoietic effects of keratinocyte growth factor. The IL-7R alpha chain is the chain shared by both TSLP and IL-7. In another study, we generated IL-7Ra transgenic mice which were used to show that constitutive expression of IL-7Ra was insufficient to support increased expansion or prevent contraction of lymphocytes during infection with Listeria monocytogenes. Overall, these studies help to improve our understanding of signaling by gc family cytokines and of TSLP. These findings clarify molecular mechanisms that are relevant to immunodeficiency, allergy, autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.