Turnbull, Cynthia2023-08-112023-08-11http://hdl.handle.net/1885/295533The immune system is an intricate network of cells tasked with defending the body from an array of foreign antigens from pathogenic microbes to toxic compounds. Self-tolerance, or the ability to distinguish between these foreign antigens and "self" antigens expressed on the body's own cells, tissues and organs is a key feature of immunity. The absence of self-tolerance induces systemic immune cell infiltration and the development of autoimmune disease. Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), is a co-inhibitory receptor which regulates T cell activation and helps maintain self-tolerance through expression on T-regulatory cells (Tregs). Haploinsufficiency of CTLA-4 mutations is associated with immune dysregulation syndrome (IDS), a complex form of autoimmunity defined by the presentation of multiple autoimmune disorders (e.g. type 1 diabetes and enteritis). Interestingly, incomplete penetrance of these mutations is quite common and proposes a role for modifier genes which exacerbate CTLA-4 deficiency while leading to other clinical manifestations not associated with the disease. Through this thesis, we describe a rare loss of function mutation in DECTIN-1 which accounts for the unusual disease features (e.g. microbial infections) of a patient with severe IDS. We also identify novel roles for DECTIN-1 in Treg induction and T effector cell expansion, suggesting functional epistasis between the receptor and CTLA-4. As such, we offer DECTIN-1 as a modifier gene for CTLA-4 haploinsufficiency and the development of severe autoimmune disease.en-AU202310.25911/HSHP-NH81