Investigating functional properties in immature CD10lo Neutrophils

Abstract

Neutrophils are the most abundant white blood cells in the circulation, being the first responders to a site of infection. Their antimicrobial arsenal includes phagocytosis, degranulation of antimicrobial peptides, production of reactive oxygen species and neutrophil extracellular traps (NETs). Whilst this antimicrobial arsenal makes neutrophils well-equipped to kill pathogens, inappropriate or over activation may also cause damage to the host. It remains unclear whether neutrophil subpopulations exist, but elevated levels of immature neutrophils released from the bone marrow have been observed in numerous inflammatory diseases including malaria and severe COVID-19. These immature neutrophils are associated with poor clinical outcome, however, there is much to elucidate in terms of their function and mechanism severe inflammatory disease. We hypothesise that immature neutrophils have altered functional properties that distinguish them from mature neutrophils. To address this we used two experimental systems. First, we used GCSF-treated donors with circulating pools of primary immature neutrophils to investigate a wholly immature population of healthy immature primary neutrophils. We found altered surface receptor expression, reduced NETs in response to the mitogen Concanavalin A and higher propensity to degranulate in neutrophils from GCSF-treated donors compared to controls. Second, we established a system for in vitro differentiation of human CD34⁺ hematopoietic stem cells into both mature (CD10⁺) and immature (CD10⁻) neutrophils. In contrast to GCSF-mobilised immature neutrophils, we found limited differences in cells of varying maturity possibly due to the increased immaturity of these cultured CD10⁺/⁻ stem cell derived neutrophils. Further investigation of functional differences between mature and immature populations is warranted in order to determine if they represent new therapeutic avenues in the context of inflammatory disease.

Date of Award	24 Jan 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Christopher Rice (Supervisor) & Borko Amulic (Supervisor)