{"id":6360,"date":"2018-07-02T14:51:47","date_gmt":"2018-07-02T18:51:47","guid":{"rendered":"https:\/\/med.virginia.edu\/pathology\/2018\/07\/02\/paige-kulling-phd-2018\/"},"modified":"2026-06-05T16:19:39","modified_gmt":"2026-06-05T20:19:39","slug":"paige-kulling-phd-2018","status":"publish","type":"post","link":"https:\/\/med.virginia.edu\/pathology\/2018\/07\/02\/paige-kulling-phd-2018\/","title":{"rendered":"Paige Kulling, PhD, 2018"},"content":{"rendered":"
\n

Characterizing and Targeting the Interferon-Gamma Signaling Pathway in T Cell Large Granular Lymphocyte Leukemia<\/h1>\n<\/div>\n

Abstract:<\/span><\/h3>\n

T cell large granular lymphocyte leukemia (T-LGLL) is a rare, chronic hematological malignancy characterized by clonal proliferation of cytotoxic CD8+ T cells due to defective apoptosis. Currently there is no cure and the main treatment options are broad immunosuppressant therapies for management of symptoms. The vast majority of T-LGLL patients require treatment at some point and thus there are efforts to identify and evaluate novel and specific therapeutics for T-LGLL. One such area of investigation is the regulation of interferon-gamma signaling. IFN-gamma is an inflammatory cytokine that is associated with worse disease progression and symptomology in multiple cancers and autoimmune diseases. Excess IFN-gamma, in the absence of infection, inhibits proliferation and induces apoptosis of healthy peripheral blood mononuclear cells (PBMCs), contributing to disease state. As a result of this, it is crucial to reduce IFN-gamma production in cancers, including T-LGLL, where patients have significantly elevated circulating levels of this pro-inflammatory cytokine compared to healthy donors. Calcitriol, the active form of vitamin D, has shown promise as an inhibitor of IFN-gamma production. Thus, we first turned our attention to evaluating calcitriol for use as an IFN-gamma inhibitor in T-LGLL. We initially assessed the effects of 24 h calcitriol treatment on TL-1 cells, the patient-derived cell line model of T-LGLL (Chapter 3). We found that calcitriol significantly decreased IFN-gamma secretion and activation of signal transducer and activator of transcription 1 (STAT1), a transcription factor that becomes activated via phosphorylation of tyrosine residue 701 (p-STAT1) in response to IFN-gamma. STAT1 also typically promotes transcription of IFN-gamma. As a result of calcitriol treatment, p-STAT1 and IFN-gamma inhibition occurred while the vitamin D receptor (VDR), a nuclear receptor and transcription factor, increased on the protein level in TL-1 cells. We next sought to elucidate the mechanism behind calcitriol-mediated reduction in IFN-gamma production and whether VDR upregulation was required for this effect (Chapter 4). We found that calcitriol reduced IFN-gamma intracellular protein and mRNA transcript levels and p-STAT1 protein levels within 4 h. Moreover, calcitriol-mediated IFN-gamma reduction was independent of p-STAT1 levels but required VDR upregulation. Our results suggested that p-STAT1 and IFN-gamma levels were regulated independently of each other, indicating a dysregulation of the canonical IFN-gamma signaling pathway. Thus, in an effort to better understand the regulation of IFN-gamma, we sought to characterize the IFN-gamma-mediated signaling pathway from IFN-gamma signaling to transcription of IFN-gamma (Chapter 5). Previous studies demonstrated that T-LGLL cells have a deficiency in suppressor of cytokine signaling 1 (SOCS1), a negative regulator of IFN-gamma-mediated signaling. SOCS1 is typically induced in response to IFN-gamma, allowing for a tightly controlled signaling process. However, despite high IFN-gamma output, T-LGLL cells exhibit significantly lower SOCS1 levels compared to normal donor cells. Therefore, T-LGLL cells are likely to be unresponsive to IFN-gamma production, allowing an unchecked production of the inflammatory cytokine as seen in other cancers. We found that TL-1 cells have a significantly lower surface protein and mRNA transcript level of the IFN-gamma receptors (IFNGR) compared to Jurkat T cells, our positive IFN-gamma responsive cell line. IFN-gamma did not induce Janus kinase 2 (JAK2) or STAT1 phosphorylation or established IFN-gamma-mediated gene targets, including IRF-1 and SOCS1, in TL-1 cells. This further demonstrated a lack of responsiveness to IFN-gamma. We found that STAT5b, but not STAT1 or STAT3, played a role in regulating IFN-gamma transcript levels. Taken together, the decrease in IFNGR levels is a plausible explanation for the excessive IFN-gamma production and lack of negative regulation observed in T-LGLL. This pathway can be targeted effectively using calcitriol to significantly reduce IFN-gamma production. As calcitriol inhibits IFN-gamma independently of STAT1, calcitriol is able to reduce IFN-gamma regardless of its interactions with STAT1, providing a potent therapeutic to reduce inflammation. This thesis is the first study to evaluate IFN-gamma signaling and a treatment aimed at specifically targeting IFN-gamma in T-LGLL. Future studies are needed to assess the efficacy of calcitriol in T-LGLL patients in the clinic.<\/P><\/p>\n

Full Dissertation<\/a><\/h3>\n","protected":false},"excerpt":{"rendered":"

Characterizing and Targeting the Interferon-Gamma Signaling Pathway in T Cell Large Granular Lymphocyte Leukemia Abstract: T cell large granular lymphocyte leukemia (T-LGLL) is a rare, chronic hematological malignancy characterized by clonal proliferation of cytotoxic CD8+ T cells due to defective apoptosis. Currently there is no cure and the main treatment options are broad immunosuppressant therapies […]<\/p>\n","protected":false},"author":1184,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":"","_members_access_role":[],"_members_access_error":"","_links_to":"","_links_to_target":""},"categories":[41],"tags":[43],"class_list":["post-6360","post","type-post","status-publish","format-standard","hentry","category-phd-defenses","tag-intranet"],"acf":false,"yoast_head":"\nPaige Kulling, PhD, 2018 - Department of Pathology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/med.virginia.edu\/pathology\/2018\/07\/02\/paige-kulling-phd-2018\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Paige Kulling, PhD, 2018 - Department of Pathology\" \/>\n<meta property=\"og:description\" content=\"Characterizing and Targeting the Interferon-Gamma Signaling Pathway in T Cell Large Granular Lymphocyte Leukemia Abstract: T cell large granular lymphocyte leukemia (T-LGLL) is a rare, chronic hematological malignancy characterized by clonal proliferation of cytotoxic CD8+ T cells due to defective apoptosis. 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