"The Role of PI3Kγ in the Immune Response" by Stephen Lanahan

The Role of PI3Kγ in the Immune Response

Date of Award

Fall 2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Lucas, Carrie

Abstract

Monogenic primary immunodeficiencies (PIDs) have uncovered how numerous genes regulate the human immune response and, therefore, provide foundational knowledge directly in humans that can be applied more broadly. Phosphoinositide 3-kinase genes are an increasingly recognized set of important genes that, when mutated, can cause PIDs. Understanding the role of immune-related genes is key to unlocking new treatments for patients in need.Chapter 1 consists of a holistic background of the lipid kinase PI3Kg. PI3Kg is a key mediator of signaling downstream of receptors and its expression is limited to immune cells. In addition to its known role in immune subsets and different diseases, Chapter 1 highlights the gaps in knowledge surrounding PI3Kg. Chapter 2 begins by identifying the first patient (Patient A.1) lacking functional PI3Kg. The clinical manifestations of Patient A.1 are modeled using “dirty” mice, which accurately recapitulate the main phenotypes of the patient’s disease. We then use these mouse models and in-vitro studies to elucidate the mechanism of the patient’s mucosal inflammation. Collectively, these findings help us better understand the role of PI3Kg in macrophages and help us identify potential therapeutic avenues for this rare disease. In Chapter 3, we investigate the defective humoral response observed in Patient A.1 and model this disease using mice lacking functional PI3Kg. Patient A.1 presented with hypogammaglobulinemia, minimal responses to vaccination, and reduced numbers of fully differentiated B cell subsets. To model this, we administer a variety of immunizations to mice lacking PI3Kg. PI3Kg is required for optimal class-switched antibody production to T-dependent (TD) immune responses. On the other hand, PI3Kg is dispensable for T- independent (TI) IgM responses. We next assessed the transcriptional profile of germinal center B cells in immunized PI3Kg knockout mice and observed fewer plasma cell gene signatures. This led us to hypothesize that PI3Kg was important for antibody secreting cell differentiation or function. Murine B cells lacking PI3Kg can activate and proliferate in- vitro post TI or TD stimulation but are unable to differentiate optimally into antibody secreting cells with anti-CD40 stimulation. We expand this finding to human antibody secreting cell differentiation using the small molecule inhibitor IPI-549. IPI-549 can reduce antigen specific class-switched antibodies in mice post TD immunization, which suggests the drug may be efficacious in clinical indications driven by pathogenic GC-derived antibodies. This study demonstrates that PI3Kg is a key component of the TD humoral response. In Chapter 4, we explore future directions for studies regarding PI3Kg and unanswered questions that arose during this thesis. Specifically, we discuss which applications would be relevant for PI3Kg inhibition or activation and present key negative data using IPI-549 in non-GC driven autoimmune models and cancer cell lines. This collective body of work provides important insights into the role of PI3Kg in the immune response and reveals new therapeutic avenues for targeting PI3Kg.

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