Author ORCID Identifier
0000-0002-0761-4967
Date of Graduation
8-2020
Document Type
Thesis (MS)
Program Affiliation
Cancer Biology
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Cassian Yee, M.D.
Committee Member
Stephanie Watowich, PhD.
Committee Member
Shao-Cong Sun, PhD.
Committee Member
Jian Hu, PhD.
Committee Member
Yejing Ge, PhD.
Abstract
Dendritic cells (DCs) are considered the most potent antigen presenting cells (APC) due to their superior capability of cross-presenting exogenous antigens to CD8+ T cell for strong adaptive immune responses. They internalize foreign antigens by phagocytosis, endocytosis or macropinocytosis, which are then processed in endosomal compartments and loaded onto MHC Class I molecules. However, the molecular mechanisms regulating exogenous antigen uptake and cross-presentation by DCs are not fully understood.
In this study, we discovered that an RNA-binding protein, Quaking (QKI) plays a pivotal role in antigen uptake by DCs. Our previous studies in neural stem cells and microglia have identified QKI as a novel regulator of phagosomes and endolysosomes, and knocking down of QKI significantly downregulates genes involved in phagosome maturation and endosome signaling. Furthermore, we have also shown that QKI interacts with a nuclear receptor, PPARδ, in multiple cell types. The QKI- PPARδ complex induces expression of a large set of genes associated with signaling in phagosome and endolysosome by binding to their promoter regions. Therefore, we hypothesize that in DCs, QKI and PPARδ mediated promotion of phagosome and endolysosome signaling can enhance antigen uptake and cross-presentation function of these cells.
Using human monocyte derived DCs, we found QKI and PPARδ to be significantly upregulated upon monocyte differentiation into DC in vitro. Our data have demonstrated that activation of QKI/PPARδ complex by PPARδ receptor agonist increases the phagocytosis activity in DCs while siRNA silencing of QKI or PPARδ impairs it. This suggests that QKI cooperates with PPARδ to enhance the antigen uptake by DCs. Our studies did not establish the role of either QKI or PPARδ in the regulation of exogenous antigen cross-presentation by DCs following uptake.
Further investigation aimed at dissecting the mechanisms by which QKI/PPARδ complex enhances antigen uptake will contribute to our current understanding of DC biology and may provide new strategies to improve DC-based immunotherapy.
Keywords
dendritic cells, antigen uptake, quaking, antigen cross-presentation