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, and previously showed that TSLP and IL-7, which share IL-7Ra as a receptor component, both drive the development of regulatory T cells, and that TSLP also signals via receptors on CD8+ T cells. In the past year, we focused on the mechanism of signal transduction of TSLP and also further clarified its role and that of gc family cytokines on survival and proliferation. Moreover, in a collaborative study, it was shown that patients suffering from atopic dermatitis but not psoriasis or lichen planus had a marked reduction of expression for the receptor for Notch, a key transcription factor signaling pathway and that the loss of Notch in keratinocytes induces the production of TSLP, which is implicated in atopic dermatitis that is associated with a myeloproliferative disorder. Overall, these studies have increase our understanding of signaling by gc family cytokines and TSLP, clarifying molecular mechanisms that are relevant to immunodeficiency, allergy, autoimmunity, and cancer, as well as related to lymphoid homeostasis.