Date of Graduation
12-2015
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Kimberly Schluns, Ph.D.
Committee Member
Dr. Willem Overwijk, Ph.D.
Committee Member
Dr. Dean Lee, M.D., Ph.D.
Committee Member
Dr. David McConkey, Ph.D.
Committee Member
Dr. Cassian Yee, M.D.
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.
Keywords
Interleukin-15, Lymphopenia, Interferon, ADAM17, Dendritic cell, Macrophage