Contribution of Lipid Kinase Vps34 to the Development and Function of Antigen Presenting Cells

Abstract

T cells of the immune system are critical for an adaptive immune response to infection. T cells are unique among immune cells in that they require an intermediate cell, termed antigen presenting cell (APC), to process and present cognate antigen bound to major histocompatibility complex (MHC) molecules to T cells for them to affect their immune function. The overarching goal of this dissertation is to elucidate the contribution that the lipid kinase Vps34 makes to the development, homeostasis, and function of two important APCs, namely thymic epithelial cells (TECs) and B cells. Vps34 is the sole class III PI3K and is significantly understudied relative to class I and II PI3Ks, especially in the context of immune cell function. Vps34 contributes to diverse cellular processes including endocytosis, vesicular trafficking, and autophagy – processes that contribute to MHC class II antigen processing and presentation. Furthermore, autophagy is a central mechanism by which cells respond to stress and maintain cellular homeostasis by delivering cytoplasmic constituents to the lysosome for recycling. The central hypothesis for this thesis project is that Vps34-mediated cellular processes maintain organellar quality control to promote the homeostasis of mature TECs and B cells and uniquely control their capacity for MHC class II-restricted antigen presentation. This hypothesis was tested in two research chapters. In chapter 2, I interrogated the intrathymic development and repertoire selection of CD4+ T cells in mice with a TEC-specific deletion of Vps34. In chapter 3, I examined the capacity of Vps34-deficient B cells to maintain mature homeostasis and participate in MHC class II-restricted T cell dependent humoral responses. This work represents the first comprehensive examination of the role Vps34 plays in TECs and B cells. The results of this thesis provide novel insights into the mechanisms governing the generation and maintenance of cells of the adaptive immune system with practical implications for the development of therapeutics that leverage adaptive immunity such as vaccines.