Stefano Travaglino
BME PhD Defense Presentation

Date: 2025-04-17
Time: 3:00PM-5:00PM
Location / Meeting Link: UAW McIntire conference room (3115), https://gatech.zoom.us/j/95147889434?pwd=BWXDNHKCJG4lpgNfNzJ88LbRDk4hla.1

Committee Members:
Cheng Zhu, PhD (Advisor); Ankur Singh, PhD; Gabe A. Kwong, PhD; Jürgen Wienands, PhD; Leslie W. Chan, PhD;


Title: Mechanobiology of B cell Immunoreceptors

Abstract:
Receptor-ligand interactions at the synapse of immune cells play a central key role in cancer and pathogen immunity allowing communication between different cells of the immune system. In follicles, B cells form immune synapses with follicular dendritic cells (FDCs) where the B cell receptor (BCR) scans the FDC surface for antigenic ligands. Upon binding to the BCR, thymus-dependent (TD) antigens are internalized by the B cell and the processed peptides are presented by major histocompatibility complex (pMHC) molecules on the B cell surface. These TD antigens are tested by the T cell receptor (TCR) of follicular T helper (TFH) cells in a process known as linked recognition. If both the B and TFH cells recognize the same TD antigen, the activated TFH cell expresses a costimulatory ligand, CD40L, which binds CD40 on B cells, communicating the successful recognition of a TD antigen peptide by the TFH cell, and thus antigen match by productive binding of both BCR and TCR. As the immune synapses formed by B cells with FDCs and T cells are mechanically rich environments, both BCR-antigen bonds and CD40-CD40L bonds experience mechanical forces. In this thesis, we uncover the role of force on interactions mediated by BCR and CD40. Naïve B cells express two different BCR isotypes, IgM and IgD, whose respective roles are poorly understood, and upon class switch recombination, B cells can express other isotypes: IgG, IgE, and IgA. While the role of different isotypes in their soluble antibody form has been extensively studied, in this thesis we discovered distinct mechanotransduction characteristics of the IgM, IgD and IgG isotypes in their membrane-bound BCR form. Furthermore, we found that mechanotransduction also governs CD40 receptor binding, and its dysregulation by CD40L mutations negatively impacts CD40 signaling and function. The importance of this finding is underscored by the fact that mutations affecting CD40–CD40L interactions cause abnormal antibody responses in immune deficiencies known as X-linked Hyper IgM syndrome (X-HIgM), where B cells are unable to undergo antibody class-switch recombination (CSR), leading to lack of long-lasting immunity to pathogens. In summary, this thesis sheds light on the mechanobiology of CD40 and BCR using highly sensitive, single molecule, single cell, and high throughput biomechanical assays. Overall, this research provides significant insights into the biophysical aspects of B cell immune receptor interactions and their implications for the adaptive immune system.