Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Primary immunodeficiencies (PID) are inherited disorders caused by single-gene defects that weaken the immune system and often result in recurrent or severe infections. More than 500 PIDs have now been genetically identified, each offering important insights about how the human immune system normally functions. Dr. Donald Vinh's lab identified a novel combined immunodeficiency caused by a mutation in ICOSLG, the gene encoding the inducible T-cell costimulatory ligand (ICOSL). Normally, ICOSL on immune cells engages ICOS on T cells to support activation and B cell help. In patients, a mutation prevents ICOSL from reaching the cell surface, impairing T-B collaboration and antibody production, leading to impaired antibody generation and recurrent bacterial infections. Yet, persistent DNA viruses (e.g., HPV, CMV) despite abundant T cells in patients remain unexplained. Our preliminary work suggests that in the absence of ICOSL, T cells skew toward regulatory T cells or central memory T cells, which may suppress immune activity and limit effective viral clearance. This project will investigate the mechanisms by which ICOSL deficiency alters T cell fate and function. Using patient-derived cells, genome editing, and advanced immune profiling, we will examine whether these T cells are suppressive or exhausted. By studying the molecular pathways underlying these processes, we aim to reveal how ICOSL normally directs the balance between viral clearance and viral tolerance. This work will provide new insight into human antiviral immunity and define the role of ICOSL in regulating T cell function. Beyond improving the understanding of this rare disorder, our findings could inform broader strategies to strengthen immune responses against chronic viral infections, where similar mechanisms of immune tolerance may be at play.