IL-2 Family Cytokines and their Receptors--Biology of the IL-7/TSLP Systems

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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, the lab co-discovered IL-2Rb in 1986, and then 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 and then in 1995 discovered 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. As detailed below, TSLP is related to IL-7. In collaboration with Harvey Lodish's lab at MIT, we previously reported the cloning of the receptor for thymic stromal lymphopoietin (TSLP), the topic of this report, and showed that the functional receptor for TSLP is TSLPR + IL7R. We then demonstrated that TSLP, in contrast 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 in a 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 also contributed 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. We also contributed to a collaboration with N. Hirasawa that reported that all-trans retinoid acid can enhance antibody production by inducing TSLP and to a study with Y. Rochman and H. Singh that TSLP signaling in CD4+ T cells can program a pathogenic Th2 state. Finally, we previously contributed to a study with K. Nagao showing that there is spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORgt+ ILCs that are located in hair follicles adjacent to sebaceous glands. The persistence of these ILCs required both IL-7 and TSLP. Thus, epithelial-derived cytokines are important for the maintenance of skin-resident ILCs that regulate microbial commensalism, with the data indicating an immune-epithelial cell relationship for regulating the barrier surface. We also previously investigated the role of TSLP in primary and recall CD8 T cell antiviral response. As noted above, TSLP acts directly on CD4+ T cells and dendritic cells to promote allergic disease (e.g., asthma and atopic dermatitis). However, the role for TSLP in CD8+ T-cell primary responses had been controversial, and its role in memory CD8+ T cell responses to secondary viral infection has been unknown. We thus had investigated the role of TSLP in primary and recall responses in mice using influenza and lymphocyte choriomeningitis virus (LCMV). TSLP limited the primary CD8+ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8+ T cells. However, this cytokine inhibited memory CD8+ T-cell responses to secondary viral infection with either influenza or acute LCMV infection. Thus, TSLP affects recall CD8+ T-cell responses following viral infection. These observations may have translational implications. In the current year, we are making use of new genetically altered mice we generated to further explore the biology of TSLP in normal and disease states. Considerable new data have been generated with a manuscript under review as well as published abstracts. We also reported that crosstalk between ILC2s and Th2 cells varies in different mouse models. By generating mice deficient in either ILC2s or Th2 cells, we found that IL-33-mediated ILC2 activation promoted the Th2 cell response to papain, whereas the Th2 response to OVA/alum immunization is dependent on TSLP but independent of ILC2s. During helminth infection, Th2 cells express IL-25, IL-33, and TSLP. 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-- both elucidating new biology and also having potential therapeutic implications.