The IL-2 receptor and related cytokine receptor systems are being studied to clarify the 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 collaboration with Harvey Lodish's lab at MIT, we previously reported the cloning of the receptor for thymic stromal lymphopoietin (TSLP). The functional receptor for TSLP is TSLPR + IL7R. We then demonstrated that TSLP, counter to reports in the literature, exerted major actions not only via dendritic cells but also via CD4+ T cells in both humans and mice, that TSLP also signals via receptors on CD8+ T cells, and showed with Scott Durum that TSLP and IL-7, which share IL-7Ra as a receptor component, both drive the development of regulatory T cells. We also showed that although TSLP and IL-7 share IL-7R, their functions are distinctive, and that TSLP promotes CD4 T cell development whereas IL-7, like IL-15, favors CD8 T cell development. We also previously showed that TSLP plays a critical role in the development of allergic lung inflammation mouse model of asthma, and that CD4+ T cells are essential for those actions. Moreover, we reported that TSLP signals via JAK1 and JAK2 rather than through a Tek family kinase, as had been suggested in the literature, to mediate the activation of STAT5 in both human and mouse T cells, and that STAT5 mediated TSLP-induced survival and proliferation of CD4+ T cells, We also showed that JAK1 associates with IL7R and JAK2 with TSLPR, clarifying the basis for TSLP signaling and providing the first example of a cytokine using the combination of JAK1 and JAK2 to mediate the activation of STAT5. We showed that dendritic cells, which were known to respond to TSLP, unexpectedly produce TSLP, including after challenge with house dust mite extract, suggesting a possibly autocrine mechanism for their responsiveness to this cytokine. Furthermore, we showed with Arya Biragyn that TSLP produced by human and mouse solid tumors contributes to progression and metastasis in breast cancer and melanoma model systems and that the cancer-romoting action of TSLP is mediated via its action on T cells, with the production of IL-10 and IL-13; with N. Hirasawa that nonanoic acid can induce TSLP and exacerbate allergic inflammation in mice; and with C. Ellison that the lack of functional TSLP receptors mitigates Th2 polarization and the establishment and growth of 4T1 primary breast tmors but has different effects on tumor quantities in the lung and brain. Moreover, with L. Pohl, we previously demonstrated that TSLP and IL-4 mediate the pathogenesis of drug-induced liver injury in mice. We continued to work on aspects of the biology of TSLP, having identified novel actions of this cytokine and in related work, we made major contributions to a study showing that T helper 1 immunity requires complement-driven NLRP3 inflammasome activity and contributed to a collaborative study that skin-derived TSLP systemically expands regulatory T cells. Moreover, we previously reported that TSLP can promote neutrophil-dependent killing of methicillin-resistant Staphylococcus aureus and Streptococcus pyogenes and that it mediates such killing via pathway(s) dependent on reactive oxygen species and complement, revealing an unappreciated action of TSLP and providing the first link between a type I cytokine and complement activation. Thus, our findings not only have elucidated new biology but also have potential therapeutic implications implications. In the current review year, we contributed to a collaboration with Dr. Hirasawa that reported that all-trans retinoid acid can enhance antibody production by inducing TSLP and to a study that TSLP signaling in CD4+ T cells can program a pathogenic Th2 state. We also have continued studies to elucidate the biology of TSLP and developed new TSLP-related knockout mouse models. Overall, these studies have increased our understanding of signaling by gc family cytokines and TSLP, clarifying molecular mechanisms that are relevant to inflammation and disease.
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