A diverse assortment of infectious pathogens and TLR agonists enhance the expression of Interleukin (IL)-15. Additionally, inducing lymphopenia enhances anti-tumor responses in an IL-15-dependent manner. Paradoxically, despite the limited expression of IL-15 during homeostasis, the role of IL-15 during the steady state is well-known, while its roles during inflammation and infections remain largely undefined. IL-15 uses a unique method of production and presentation to support the development and homeostasis of NK and CD8 T cells. IL-15 is produced with its high affinity IL-15Rα and this IL-15Rα/IL-15 complex is shuttled to the cell surface where it is presented in-trans or cleaved into soluble cytokine/receptor complexes. Unfortunately, little is known about the mechanisms generating soluble IL-15 complexes. I set out to elucidate the mechanisms responsible for inducing sIL-15 complexes to test my hypothesis that Type I IFN signaling and ADAM17 are necessary for generating sIL-15 complexes. In Bone marrow dendritic cells, Type I Interferon (IFN) directly regulates the cleavage of sIL-15 complexes using the metalloprotease ADAM17. Mice with the conditional deletion of ADAM17 or a deficiency in IFN signaling led to the surprising discovery that neither Type I IFN signaling nor ADAM17 expression are required in vivo for inducing sIL-15 complexes. Interestingly, VSV infection enhances sIL-15 complexes in the absence of both IFN and CD40 signaling pathways, indicating multiple redundant mechanisms generate sIL-15 complexes. I discovered a shared mechanism of enhanced IL-15 transpresentation common to all types of lymphopenia, while only forms of lymphopenia associated with inflammation display increases in sIL-15 complexes. The optimal production of sIL-15 complexes in response to total-body irradiation (TBI) required the activation of both the IFN and STING pathways, indicating a dominant role for inflammatory cell death. Utilizing an adoptive transfer model, I identified a novel role for lymphopenia-induced inflammatory IL-15 on the proliferation of CD8 memory T cells. Overall, I’ve demonstrated a diverse assortment of stimuli utilize a variety of pathways and cell types to induce the generation of sIL-15 complexes. These findings lead me to conclude that the increase in sIL-15 complexes is a common event during conditions involving inflammation and immune activation likely contributing to memory CD8 T cell responses.
","abstract_html":"<p>A diverse assortment of infectious pathogens and TLR agonists enhance the expression of Interleukin (IL)-15. Additionally, inducing lymphopenia enhances anti-tumor responses in an IL-15-dependent manner. Paradoxically, despite the limited expression of IL-15 during homeostasis, the role of IL-15 during the steady state is well-known, while its roles during inflammation and infections remain largely undefined. IL-15 uses a unique method of production and presentation to support the development and homeostasis of NK and CD8 T cells. IL-15 is produced with its high affinity IL-15Rα and this IL-15Rα/IL-15 complex is shuttled to the cell surface where it is presented in-trans or cleaved into soluble cytokine/receptor complexes. Unfortunately, little is known about the mechanisms generating soluble IL-15 complexes. I set out to elucidate the mechanisms responsible for inducing sIL-15 complexes to test my hypothesis that Type I IFN signaling and ADAM17 are necessary for generating sIL-15 complexes. In Bone marrow dendritic cells, Type I Interferon (IFN) directly regulates the cleavage of sIL-15 complexes using the metalloprotease ADAM17. Mice with the conditional deletion of ADAM17 or a deficiency in IFN signaling led to the surprising discovery that neither Type I IFN signaling nor ADAM17 expression are required <em>in vivo</em> for inducing sIL-15 complexes. Interestingly, VSV infection enhances sIL-15 complexes in the absence of both IFN and CD40 signaling pathways, indicating multiple redundant mechanisms generate sIL-15 complexes. I discovered a shared mechanism of enhanced IL-15 transpresentation common to all types of lymphopenia, while only forms of lymphopenia associated with inflammation display increases in sIL-15 complexes. The optimal production of sIL-15 complexes in response to total-body irradiation (TBI) required the activation of both the IFN and STING pathways, indicating a dominant role for inflammatory cell death. Utilizing an adoptive transfer model, I identified a novel role for lymphopenia-induced inflammatory IL-15 on the proliferation of CD8 memory T cells. Overall, I’ve demonstrated a diverse assortment of stimuli utilize a variety of pathways and cell types to induce the generation of sIL-15 complexes. These findings lead me to conclude that the increase in sIL-15 complexes is a common event during conditions involving inflammation and immune activation likely contributing to memory CD8 T cell responses.</p>","abstract_has_math":false,"creators":["Anthony, Scott"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Dr. Kimberly Schluns, Ph.D.","Dr. Willem Overwijk, Ph.D.","Dr. Dean Lee, M.D., Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-12-01T08:00:00Z","date_published":"2015-12-01T08:00:00Z","updated_at":"2026-07-24T05:48:59Z","subjects":["Interleukin-15","Lymphopenia","Interferon","ADAM17","Dendritic cell","Macrophage","Immunity","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/633","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dr. Kimberly Schluns, Ph.D.","Dr. Willem Overwijk, Ph.D.","Dr. Dean Lee, M.D., Ph.D."]},{"key":"dc:creator","label":"Author","values":["Anthony, Scott"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2016-11-10T08:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Interleukin-15","Lymphopenia","Interferon","ADAM17","Dendritic cell","Macrophage","Immunity","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/633"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["A diverse assortment of infectious pathogens and TLR agonists enhance the expression of Interleukin (IL)-15. Additionally, inducing lymphopenia enhances anti-tumor responses in an IL-15-dependent manner. Paradoxically, despite the limited expression of IL-15 during homeostasis, the role of IL-15 during the steady state is well-known, while its roles during inflammation and infections remain largely undefined. IL-15 uses a unique method of production and presentation to support the development and homeostasis of NK and CD8 T cells. IL-15 is produced with its high affinity IL-15Rα and this IL-15Rα/IL-15 complex is shuttled to the cell surface where it is presented in-trans or cleaved into soluble cytokine/receptor complexes. Unfortunately, little is known about the mechanisms generating soluble IL-15 complexes. I set out to elucidate the mechanisms responsible for inducing sIL-15 complexes to test my hypothesis that Type I IFN signaling and ADAM17 are necessary for generating sIL-15 complexes. In Bone marrow dendritic cells, Type I Interferon (IFN) directly regulates the cleavage of sIL-15 complexes using the metalloprotease ADAM17. Mice with the conditional deletion of ADAM17 or a deficiency in IFN signaling led to the surprising discovery that neither Type I IFN signaling nor ADAM17 expression are required in vivo for inducing sIL-15 complexes. Interestingly, VSV infection enhances sIL-15 complexes in the absence of both IFN and CD40 signaling pathways, indicating multiple redundant mechanisms generate sIL-15 complexes. I discovered a shared mechanism of enhanced IL-15 transpresentation common to all types of lymphopenia, while only forms of lymphopenia associated with inflammation display increases in sIL-15 complexes. The optimal production of sIL-15 complexes in response to total-body irradiation (TBI) required the activation of both the IFN and STING pathways, indicating a dominant role for inflammatory cell death. Utilizing an adoptive transfer model, I identified a novel role for lymphopenia-induced inflammatory IL-15 on the proliferation of CD8 memory T cells. Overall, I’ve demonstrated a diverse assortment of stimuli utilize a variety of pathways and cell types to induce the generation of sIL-15 complexes. These findings lead me to conclude that the increase in sIL-15 complexes is a common event during conditions involving inflammation and immune activation likely contributing to memory CD8 T cell responses.
"]},{"key":"dc:title","label":"Title","values":["Determining The Mechanisms Generating Soluble Il-15 Complexes"]}]}],"canonical_facts":{"dc:contributor":["Dr. Kimberly Schluns, Ph.D.","Dr. Willem Overwijk, Ph.D.","Dr. Dean Lee, M.D., Ph.D."],"dc:creator":["Anthony, Scott"],"dc:date.available":["2016-11-10T08:00:00Z"],"dc:description.abstract":["A diverse assortment of infectious pathogens and TLR agonists enhance the expression of Interleukin (IL)-15. Additionally, inducing lymphopenia enhances anti-tumor responses in an IL-15-dependent manner. Paradoxically, despite the limited expression of IL-15 during homeostasis, the role of IL-15 during the steady state is well-known, while its roles during inflammation and infections remain largely undefined. IL-15 uses a unique method of production and presentation to support the development and homeostasis of NK and CD8 T cells. IL-15 is produced with its high affinity IL-15Rα and this IL-15Rα/IL-15 complex is shuttled to the cell surface where it is presented in-trans or cleaved into soluble cytokine/receptor complexes. Unfortunately, little is known about the mechanisms generating soluble IL-15 complexes. I set out to elucidate the mechanisms responsible for inducing sIL-15 complexes to test my hypothesis that Type I IFN signaling and ADAM17 are necessary for generating sIL-15 complexes. In Bone marrow dendritic cells, Type I Interferon (IFN) directly regulates the cleavage of sIL-15 complexes using the metalloprotease ADAM17. Mice with the conditional deletion of ADAM17 or a deficiency in IFN signaling led to the surprising discovery that neither Type I IFN signaling nor ADAM17 expression are required in vivo for inducing sIL-15 complexes. Interestingly, VSV infection enhances sIL-15 complexes in the absence of both IFN and CD40 signaling pathways, indicating multiple redundant mechanisms generate sIL-15 complexes. I discovered a shared mechanism of enhanced IL-15 transpresentation common to all types of lymphopenia, while only forms of lymphopenia associated with inflammation display increases in sIL-15 complexes. The optimal production of sIL-15 complexes in response to total-body irradiation (TBI) required the activation of both the IFN and STING pathways, indicating a dominant role for inflammatory cell death. Utilizing an adoptive transfer model, I identified a novel role for lymphopenia-induced inflammatory IL-15 on the proliferation of CD8 memory T cells. Overall, I’ve demonstrated a diverse assortment of stimuli utilize a variety of pathways and cell types to induce the generation of sIL-15 complexes. These findings lead me to conclude that the increase in sIL-15 complexes is a common event during conditions involving inflammation and immune activation likely contributing to memory CD8 T cell responses.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/633"],"dc:subject":["Interleukin-15","Lymphopenia","Interferon","ADAM17","Dendritic cell","Macrophage","Immunity","Medicine and Health Sciences"],"dc:title":["Determining The Mechanisms Generating Soluble Il-15 Complexes"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:48:59Z"}