Aging Narrows Human B1-like Cell Repertoire and Impairs Defense Against Encapsulated Pathogens 2256562

Abstract Introduction B1-like B cells are an innate-like subset of human B cells that produce natural antibodies essential for early defense against encapsulated bacterial pathogens such as Streptococcus pneumoniae. A diverse B1-like cell repertoire is critical for robust immune responses, and reduced repertoire diversity has been implicated in the age-associated decline of innate immunity. However, the impact of aging on human B1-like cell frequency and repertoire diversity remains poorly defined. Methods In this study, we examined B1-like B cells from healthy younger and older adults using multicolor flow cytometry and single-cell B cell receptor (BCR) repertoire analysis using semi-nested RT-PCR. Results Our results revealed a significant age-associated decline in circulating B1-like B cells, accompanied by a marked reduction in phosphorylcholine (PC)-specific B1-like cells–an antigenic determinant commonly present on bacterial and self-lipids. Repertoire profiling demonstrated a substantial loss of diversity in older individuals, characterized by reduced clonal expansion and diminished light-chain gene coherence. In contrast, younger donors exhibited a broader, more polyclonal B1-like repertoire with frequent PC-specific clones linked to natural protective antibodies. These findings indicate that aging induces both quantitative and qualitative impairments in the B1-like B cell compartment, leading to “holes” in the natural antibody repertoire and weakened defense against encapsulated bacteria. Conclusion Together, these results identify the age-related loss of B1-like cell diversity as a key mechanism underlying impaired humoral protection in older adults and highlight the need for strategies to preserve or restore this critical B cell subset to enhance resistance to pneumococcal and other bacterial infections in aging populations. Funding Source NIH Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)