Research

The Laidlaw laboratory studies the development and function of memory B cells in disease settings, focusing on the extracellular signals and transcription factors regulating this process.

Transcriptional regulation of memory B cell development

Memory B cells (MBCs) are essential for the establishment of protective immunity following viral infection. MBCs undergo affinity maturation upon repeated viral encounter facilitating the development of broadly reactive MBCs capable of mediating heterosubtypic immunity. However, broadly reactive MBCs rarely develop naturally due to a bottleneck in the number of MBCs that undergo diversification upon viral challenge. We aim to develop new approaches to overcome this bottleneck through the identification of pathways critical for MBC development. The focus will be on pathways regulating the expression of transcription factors necessary for MBC development and function. We will test the hypothesis that modulating the expression of key transcription factors will allow MBCs to better participate in recall responses and promote enhanced heterosubtypic immunity. To do this, we will employ cutting-edge genetic approaches to specifically modulate gene expression in germinal center B cells to determine: 1) pathways regulating expression of transcription factors promoting MBC development, 2) downstream targets of key transcriptions factors, and 3) how modulation of these pathways impact MBC function. The identification of pathways controlling MBC development would represent a major breakthrough not only for the development of vaccines capable of better eliciting a protective MBC response, but also for the treatment of diseases in which MBCs play a pathological role such as allergy and autoimmunity.

Development and function of tissue-resident memory B cell development

Influenza is an acute respiratory infection that is responsible for up to 650,000 deaths and 3-5 million cases of severe illness worldwide each year. While vaccination can prevent disease, seasonal flu vaccine efficacy ranges from 10-60% resulting in an urgent need to design broadly protective influenza vaccines. Memory B cells in the lungs can provide protection against influenza challenge, with this population possessing an elevated frequency of cross-reactive B cells capable of mediating heterosubtypic protection. We seek to investigate the processes regulating the development, maintenance, and reactivation of influenza-specific lung-resident memory B cells. The aims of this project include: 1) Investigate the mechanisms underlying B cell migration to and maintenance within the lungs; 2) Determine the transcription factors regulating lung memory B cell development and function and; 3) Explore the requirements for memory B cell reactivation within the lungs and their contribution to long-term protective immunity. The proposed research will significantly increase understanding of how lung-resident memory B cells develop and function with the long-term goal being to harness this knowledge to design vaccines better able to elicit these cells. We also are highly interested in extending this work to evaluate how the tissue microenvironment shapes the development and function of memory B cells.