Mechanosensing through the b cell antigen receptor

The National Institute of Allergy and Infectious Diseases awarded Georgia TECH Research Corp $410,864 on February 19, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate mechanosensing through the B cell antigen receptor.

The recipient will characterize isotype-dependent in situ affinities and force-dependent lifetimes of B cell antigen receptor (BCR)–antigen bonds at the single-cell and single-bond level, correlating concurrent calcium flux measurements with biophysical measurements. The work aims to test the B cell mechanosensory hypothesis by determining how affinity thresholds translate into force thresholds and how mechanical force modulates BCR signaling. The research addresses fundamental gaps in understanding how antigen binding initiates BCR signaling and explains the functional advantage of co-expressing two BCR isotypes on mature B cells, which carry identical antigen specificity and affinity but may differ in mechanosensitivity.

The period of performance runs from the award date through January 31, 2028. Work is performed in Georgia.

Abstract

Signaling through the b cell antigen receptor (BCR) is indispensable for b lymphocyte maturation, activation and differentiation as IT governs the initiation of transcriptional programs associated with b cell activation and fate decisions, as well as the BCR-dependent processing of antigen and presentation of antigen to t cells. The dysregulation of BCR signaling results in immunodeficiency, autoimmunity or tumorigenesis. However, despite its pivotal relevance to health and disease, the mechanisms by which antigen binding initiates BCR signaling are still incompletely understood. Upon maturation, naïve b cells express both IGM and IGD isotypes of BCR, which have identical specificity and affinity for antigen. Yet, the functional advantage to CO-express two BCR isotypes with equal affinities on every mature b cell remains puzzling. After antigen stimulation in the germinal center (GC), b cells differentiate and undergo somatic hypermutation as well as class switch recombination, by which their bcrs greatly increase affinity for antigen and change isotypes to IGG, IGE, and IGA. IT has been shown that GC b cells have intrinsically higher-affinity thresholds for BCR signaling and pull on bcrs to extract from dendritic cells bound antigens mechanically. However, IT is not known how the affinity threshold translates into force threshold and how mechanical force modulates BCR signaling. Using a set of mechanoimmunological concepts, ideas, approaches, and tools, we propose to investigate these fundamental questions under two specific aims, aim 1 will test the b cell mechanosensory hypothesis at the single-cell and single-bond level by characterizing theisotype-dependent in situ affinities and force-dependent lifetimes of BCR-antigen bonds and by correlating concurrently measured calcium (CA2+) fluxes in b cells with the biophysical measurements. Aim 2 will test the b cell mechanosensory hypothesis at the cell population level by characterizing theisotype-dependent b cell endogenous forces on BCR-antigen bonds, by measuring theisotype-dependent calcium fluxes in b cells induced by BCR-antigen engagement, and by determining the force requirement forisotype-dependent calcium fluxes in b cells. The proposed research holds the promise to provide the conceptual framework, design principles, and engineering strategies to harness the power of the b cell adaptive immune system to combat diseases ranging from viral infections, auto-immune disorders, to cancer.