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 reported 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. Having preveiously demonstrated that TSLP receptors are expressed on mouse and human CD4+ T cells, we importantly demonstrated and reported that they are also expressed on CD8+ T cells. Thus, in addition to expression of TSLP receptors on dendritic cells and mast cells, our data reveal the presence of TSLP receptors on these two major populations of T cells. We also showed that TSLP could activate STAT5 and AKT as well as induce BCL2 expression in these cells. Corresponding, TSLP also promoted CD8+ T cell survival in vitro and in vivo, and could maintain these cells even in the absence of IL-7, revealing important roles for TSLP in lymphoid homeostasis. 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.
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