Determining The Mechanisms Generating Soluble Il-15 Complexes

<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>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Anthony, Scott

Contributors dc:contributor

• Dr. Kimberly Schluns, Ph.D.
• Dr. Willem Overwijk, Ph.D.
• Dr. Dean Lee, M.D., Ph.D.

• Interleukin-15
• Lymphopenia
• Interferon
• ADAM17
• Dendritic cell
• Macrophage
• Immunity
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/633

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1668