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Neutrophils promote T cell activation in HIV infection through the regulated release of CD44 bound, cell surface Galectin-9

  • Author / Creator
    Dunsmore, Garett John
  • Neutrophils are the most abundant leukocyte in the human immune system constituting 50-80% of all white blood cells in the peripheral blood. Neutrophils are potent source of protective immune responses through the production of reactive oxygen species (ROS), extracellular trap formation, cytokine release, and phagocytosis of pathogens. Previous work has investigated the ability of neutrophils to impact T cell function through activation (HLA-DR, CD40, CD80, CD86, and ROS) or inhibition (Arginase-1, PDL-1) in HIV infection. Despite these studies, the interaction between neutrophils and T cells in the context of HIV infection remains a largely unexplored field that may reveal crucial implications that benefit human health. Our study identifies a novel mechanism by which activated neutrophils in HIV infection promote increased activation of T cells by shedding Galectin-9 (Gal-9). In addition to this we propose that exogenous Gal-9 binds to cell surface CD44 on T cells to promote LCK activation and subsequentially enhances T cell activation. Neutrophils also bind Gal-9 to surface CD44, which does not appear to promote cell signalling. Instead, we identify a novel mechanism of Gal-9 shedding by stimulated neutrophils. Unstimulated neutrophils express high levels of surface Gal-9 that is bound to CD44, upon stimulation neutrophils depalmitoylate CD44 and induce its movement out of the lipid raft. This process causes the release of Gal-9 from the surface of neutrophils. Furthermore, this process is regulated by the activity of glycolysis and can be inhibited by IL-10. Together our data reveal a novel mechanism of Gal-9 shedding from the surface of neutrophils. This could explain the elevated plasma Gal-9 levels in HIV-infected individuals as the underlying mechanism of the well-characterized chronic immune activation. This study provides a novel role for the Gal-9 in HIV pathogenesis.

  • Subjects / Keywords
  • Graduation date
    Spring 2021
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-b0qz-yv19
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.