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). 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. 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 lung inflammation mouse model of asthma, and that CD4+ T cells are essential for its action in that model. In the previous year, 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 to mediate the activation of STAT5 in both human and mouse primary T cells, and that STAT5 mediated TSLP-induced survival and proliferation of CD4+ T cells. We showed that JAK1 associates with IL7R and JAK2 with TSLPR, thus clarifying 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 previously demonstrated 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. With Arya Biragyn, we also demonstrated 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. In the past year, in a collaborative study with Dr. C. Ellison, it was reported 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. In the previous year, with N. Hirasawa in Japan, we reported that TSLP responsiveness was required for palifermin-mediated protection from graft versus host disease and that moreover, TSLP was induced by xylene and associated with exacerbation of picryl chloride-induced allergic inflammation, and in the past year, additional studies were reported that TSLP production was induced by nonanoic acid, with exacerbation of allergic inflammation in mice. 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.
|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 :|
|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|
|Rochman, Yrina; Spolski, Rosanne; Leonard, Warren J (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9:480-90|
|Rochman, Yrina; Leonard, Warren J (2008) The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis. J Immunol 181:7699-705|