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 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 plus IL7R. We then demonstrated that TSLP, counter to the sense of the literature, exerted major actions via CD4+ T cells in both humans and mice, and previously 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, and that TSLP also signals via receptors on CD8+ T cells. We also showed that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the functions of TSLP and IL-7 are distinctive. We showed that TSLP promotes CD4 T cell development whereas IL-7 and IL-15 favor 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, Moreover, we 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 also 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 previously 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 demonstrated that TSLP and IL-4 mediate the pathogenesis of drug-induced liver injury in mice. In the past year, we have continued to work on aspects of the biology of TSLP, making substantial progress on novel actions of this cytokine. In related work, we made major contributions to a study showing that T helper 1 immunity requires complement-driven NLRP3 inflammasome activity. Overall, these studies have increased 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 to lymphoid homeostasis and inflammation.

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U.S. National Heart Lung and Blood Inst
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Rochman, Yrina; Dienger-Stambaugh, Krista; Richgels, Phoebe K et al. (2018) TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state. Sci Signal 11:
Hatayama, Takahiro; Segawa, Ryosuke; Mizuno, Natsumi et al. (2018) All-Trans Retinoic Acid Enhances Antibody Production by Inducing the Expression of Thymic Stromal Lymphopoietin Protein. J Immunol 200:2670-2676
Leichner, Theresa M; Satake, Atsushi; Harrison, Victor Sanoe et al. (2017) Skin-derived TSLP systemically expands regulatory T cells. J Autoimmun 79:39-52
West, Erin E; Spolski, Rosanne; Kazemian, Majid et al. (2016) A TSLP-complement axis mediates neutrophil killing of methicillin-resistant Staphylococcus aureus. Sci Immunol 1:
Arbore, Giuseppina; West, Erin E; Spolski, Rosanne et al. (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4? T cells. Science 352:aad1210
Proctor, William R; Chakraborty, Mala; Fullerton, Aaron M et al. (2014) Thymic stromal lymphopoietin and interleukin-4 mediate the pathogenesis of halothane-induced liver injury in mice. Hepatology 60:1741-52
Usategui, Alicia; Criado, Gabriel; Izquierdo, Elena et al. (2013) A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis. Ann Rheum Dis :
Yamashita, Saori; Segawa, Ryosuke; Satou, Nozomi et al. (2013) Induction of thymic stromal lymphopoietin production by nonanoic acid and exacerbation of allergic inflammation in mice. Allergol Int 62:463-71
Erdmann, R B; Gartner, J G; Leonard, W J et al. (2013) Lack of functional TSLP receptors mitigates Th2 polarization and the establishment and growth of 4T1 primary breast tumours but has different effects on tumour quantities in the lung and brain. Scand J Immunol 78:408-18
Zhang, Jianhong; Chen, Zhilin; Fritz, Jorg H et al. (2012) Unusual timing of CD127 expression by mouse uterine natural killer cells. J Leukoc Biol 91:417-26

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