Author ORCiD
Date of Award
2026
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Michel C. Nussenzweig
Keywords
immune response, immune complexes, Fc gamma receptors, B cells, antibodies
Abstract
Upon pathogen exposure, two main lines of defense are sequentially activated: the innate immune response and the adaptive immune response. The innate immune response is the first line of defense, and consists mainly of myeloid cells that are quickly activated within hours to days to engage in a non-specific manner. This broad response is followed by the adaptive immune response, which progresses more slowly but is capable of generating pathogen-specific immunity. Together, the innate and adaptive immune systems coordinate and facilitate pathogen clearance. A novel feature of the adaptive immune response is the formation of immune memory which facilitates a more rapid and efficient response upon re-exposure to the same or similar pathogen. This memory can be cellular, such as memory B & T lymphocytes, or humoral, such as antibodies. Memory B and T lymphocytes have been well-characterized to differentiate into various effector cells upon re-exposure, whereas antibodies are classically known to block and neutralize circulating pathogen via various effect or functions. Additionally, accumulating evidence has suggested that antibodies themselves are capable of enhancing or suppressing endogenous immune responses; however, the exact manner and mechanisms by which antibodies exert this modulation remains unclear. The first part of this thesis focuses on defining how antibodies can modulate the development of a polyclonal immune response. Infusion of a monoclonal antibody prior to immunization with its cognate protein antigen resulted in two key observations. Firstly, antibody can increase the overall magnitude of the germinal center (GC) and plasmablast (PB) response. Secondly, this enhancement is accompanied by a simultaneous decrease in the fraction of these compartments with measurable antigen binding. This modulation capability was conserved with alternative antigen-antibody combinations, suggesting it is a broadly applicable feature of immune responses. Examination of the mechanisms that drive the enhanced magnitude of the GC and PB response elucidated that while T cells are required for this modulation, no statistically significant differences were observed in T cell compartments themselves, such as early expanding T cells and T follicular helper cells (Tfh). Moreso, further experimentation illuminated that this enhancement capability was largely independent of complement receptors 1 and 2 (CR1/2) but was instead dependent on interactions with Fc gamma receptors (FcγRs). Both immunohistochemistry and flow cytometry revealed that infused antibody generated immune complexes (ICs)are retained across the lymph node on classical IC retaining follicular dendritic cells (FDCs) and hematopoietic cells such as macrophages and dendritic cells, but that this IC retention is significantly reduced in FcγR deficient mice. Altogether, the data suggests that antibody can facilitate enhanced IC retention and larger magnitude GC and PB responses in a FcγR dependent manner. Despite the FcγR dependence of the antibody-mediated enhanced magnitude of the GC and PB response, the reduction in the fraction of detectable antigen-binding cells in these compartments was found to be independent of FcγRs. Notably, this reduction was observed throughout the seeding phase of the response, suggesting that antibody can recruit a more affinity-diverse pool of B cells. Altogether, antibody via FcγR dependent and independent mechanisms can influence both the magnitude and quality of the immune response.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Cipolla, Melissa, "Antibody-Mediated Modulation of Polyclonal Immune Responses" (2026). Student Theses and Dissertations. 849.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/849
Comments
A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy