Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Craft, Joseph
Abstract
The immune system functions as the major defender against pathogenic challenges but can also cause damage to host tissues. Humoral immunity, mediated by diverse B cell subsets, is a crucial component of immunological memory and forms the basis of long-lasting immunological protection induced by most existing vaccines. On the flip side, B cell response is a key link in the cascade of events leading to autoimmunity and immunopathology. Atypical memory B cells (also known as age-associated B cells, hereafter ABCs) is a recently described population of B cells strongly associated with pathological immune functions, both in patients with autoimmune diseases and in individuals experiencing immunopathology following infections. While many studies focused on the potentially detrimental effects of the ABC response, with accumulating evidence implicating ABCs as a pathogenic subset capable of driving tissue injuries, it is equally important to understand the potential beneficial functions mediated by ABCs, which presumably led to their preservation throughout evolution. Similarly unclear are the developmental pathways preferentially utilized by ABCs that drive their divergence from other B cell subsets, crucial for precise future targeting of this population in therapies against infection and autoimmunity. The work presented in this dissertation summarizes our investigations into the developmental pathways and protective functions of ABCs, utilizing mouse models of acute viral infections. We took a biographical approach in studying ABCs, tracing key events in their lifetime and following their migratory trajectory to interrogate how their generation and functional output are determined by other factors present in the surrounding local environment. Chapter 1 provides an overview of the orchestration of humoral immune responses through a spatiotemporal lens. Chapter 2 presents the key early events leading to the emergence of ABCs in the spleen following viral infections, with a particular focus on the encounter and exchange of signals with T follicular helper (Tfh) cells. Chapter 3 examines ABCs’ relationship with the germinal center (GC) reaction, a crucial pathway in the generation of long-lasting protective humoral immunity. Chapter 4 explores how ABCs accumulate in non-lymphoid organs where they may mediate protection or tissue damage under different immunological contexts. Chapter 5 traces ABCs’ migration as they mature into memory cells and determines their relative contribution among total B cells to humoral memory, exploring how ABCs’ unique residency and localization may be linked to their activities. Finally, Chapter 6 highlights key questions surrounding ABCs that await answers. Altogether, our work captured the major events leading to the generation and functions of ABCs, elucidated the underlying molecular pathways, and identified key processes for future therapeutic targeting.
Recommended Citation
Song, Wenzhi, "Spatiotemporal Regulation of Atypical B Cell Memory" (2023). Yale Graduate School of Arts and Sciences Dissertations. 943.
https://elischolar.library.yale.edu/gsas_dissertations/943
