Self-reactive T cells cause many autoimmune diseases, and can also trigger serious autoimmune side-effects in cancer patients undergoing immunotherapy. T cell activation normally occurs upon interaction with antigen-presenting cells (APCs) expressing surface ligands for the T cell receptor and the costimulatory receptor CD28. Surface CTLA4 expressed by activated T cells or regulatory T cells (Tregs) dampens T cell activation and restrains autoimmunity by outcompeting CD28 for their shared costimulatory ligands CD80 and CD86 expressed on the APC surface. Recombinant homodimeric CTLA4-Ig fusion proteins also bind CD80 and CD86 to prevent T cell costimulation, and CTLA4-Ig therapies including abatacept are widely used clinically for autoimmune disease and organ transplant rejection. In 2018 it was reported that CD80 and the coinhibitory ligand PDL1 interact in cis on the same APC surface, but how this intersects with the CTLA4 checkpoint was unclear. In recent unpublished work we have identified a novel mechanism whereby cell surface CTLA4 and CTLA4-Ig therapies influence CD80 and PDL1 to contribute to T cell suppression. This project will use cell-based expression systems to determine the precise molecular details of this mechanism, and mouse models of autoimmunity and cancer to test whether this mechanism contributes to CTLA4 immunosuppression in vivo. These studies will also investigate the immunosuppressive properties of a series of rationally designed CTLA4-Ig fusion proteins with mechanisms distinct to current therapies. We anticipate that an improved understanding of this new mechanism, which links the critically important CTLA4 and PD1 immune checkpoints, will lead to novel therapeutic strategies that improve control of T cell activity in autoimmunity and cancer.
Autoimmunity, immunology, T cells, cancer, immunotherapy, myeloid, CTLA4, immunosuppression, therapy, immune checkpoints, Human Pathology
Australian Centre for Blood Diseases (ACBD)
Masters by research
Top-up scholarship funding available
Australian Centre for Blood Diseases