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 the Lodish lab, we previously reported the cloning of the receptor for thymic stromal lymphopoietin (TSLP) 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. 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 development of allergic asthma in a mouse model system. In the past year, we focused on the mechanism of signal transduction of TSLP. Using a series of JAK kinase or Tek kinase deficient cell lines and siRNA constructs, we demonstrated and reported that TSLP signals via JAK1 and JAK2 rather than through a Tek family kinase (as had been suggested in the literature). TSLP via these JAKs activates STAT5, including in both human and mouse primary T cells. We also demonstrated the importance of STAT5 for TSLP-mediated survival and proliferation of CD4+ T cells. We showed that JAK1 associates with IL7R and JAK2 with TSLPR. Our findings clarified the basis for TSLP signaling and provided the first example of a cytokine using the combination of JAK1 and JAK2 to mediate the activation of STAT5. We also demonstrated for the first time that dendritic cells, which potently respond to TSLP, unexpectedly produce TSLP, suggesting a possibly autocrine mechanism for their responsiveness to this cytokine. We demonstrated that when mice were challenged with house dust mite extract, dendritic cells produced even more TSLP than did epithelial cells, underscoring the potency of the response. In a study with Arya Biragyn, we also demonstrated that TSLP is produced by human and mouse solid tumors and plays an essential role in cancer progression and metastasis in breast cancer and melanoma model systems. We showed that the cancer-romoting action of TSLP was mediated via its action on T cells, with the production of IL-10 and IL-13. We also contributed to studies that demonstrate that TSLP responsiveness was required for palifermin-mediated protection from graft versus host disease and that TSLP was induced by xylene and associated with exacerbation of picryl chloride-induced allergic inflammation. 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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Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$834,964
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
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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 :
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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
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
Satou, Nozomi; Ishihara, Kenji; Hiratsuka, Masahiro et al. (2012) Induction of thymic stromal lymphopoietin production by xylene and exacerbation of picryl chloride-induced allergic inflammation in mice. Int Arch Allergy Immunol 157:194-201
Oh, Min-Hee; Oh, Sun Young; Yu, Jinho et al. (2011) IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin. J Immunol 186:7232-42

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