CReativeLipid · Role of CD1c-reactive T cells and lipid antigens in post-streptococcal disease

Most T cell immunology knowledge is centered on T cell receptor (TCR) recognition of peptides presented by major histocompatibility complex (MHC) molecules. MHC class I-like CD1 proteins present lipid antigens to T cells, but it is becoming increasingly clear that the rules of lipid engagement show fundamental divergence from those of peptide recognition. As CD1 proteins are relatively monomorphic, solving the fundamental biology of lipid recognition opens the potential for wide therapeutic benefit.Group A Streptococcus (GAS) infection is associated with multiple autoimmune sequelae, yet the disease mechanisms are largely unexplained. Recent increases in GAS infection globally have re- emphasized the major unmet medical need, and driven focus on capitalizing on the therapeutic window prior to the onset of post-streptococcal autoimmunity. I hypothesize that lipid antigens derived during GAS infection break immune tolerance through molecular mimicry of self-lipids and contribute to disease.This proposal harnesses multiple recent technological advances to investigate both CD1c mechanisms and translational implications of lipid-mediated reactivity in humans. I will examine CD1c tissue immunology pathways using human tonsils, a common GAS infection site. GAS- mediated CD1c-relevant cellular and molecular mechanisms will be studied through T cell and lipid antigen discovery and will develop therapeutic targeting approaches. Identified mechanisms will be further studied in patients with post-streptococcal glomerulonephritis (PSGN), informing disease relevant host-pathogen interactions.Access to patient samples, alongside established experimental platforms and a strong collaboration network places me well to address fundamental immunological mechanisms and facilitate preventive strategies for post-streptococcal disease, as well as enabling the wider field to reach the point of industry engagement to drive patient benefit.