Novel modulators of CTLA-4 regulation and human autoimmunity

Patients suffering from T-cell mediated autoimmunity exhibit self-reactivity of their T lymphocytes, suffering immune reactions against their own cells and tissues which often results in life-threatening conditions from early age. Despite major advancements in understanding the development of autoimmune diseases, many aspects of the breakdown of immunological tolerance remain elusive. CTLA-4 is a co- inhibitory receptor in T cells with a major role in controlling immune responses. Conditions with reduced CTLA-4, for example due to genetic mutations, were found causative for compromising a normal T-cell regulatory response, resulting in autoimmune attacks. My preliminary work aimed at finding chemical drugs that are able to increase CTLA-4 in blood-derived T cells of healthy individuals and patients with inherited CTLA-4 defects. I focused on drugs with known modes of action, which allowed me to identify novel interactions between chemically-perturbed pathways and the regulation of CTLA-4 in T cells. Concomitant with biological findings of general T-cell function, studying clinically approved drugs provided the advantage of relating my results to potential novel therapeutics for these patients. Through my preliminary work, I found fundamental evidence for a novel mode of action of a biomolecule that has shown therapeutic benefits in other autoimmune disorders. Still, its mechanism of immunosuppression in T cells has remained entirely elusive. I now found a novel mode of action with increasing CTLA-4 on T cells, providing a long-sought molecular explanation for its immunosuppressive effects. I aim at providing detailed mechanistic understanding of these processes by using state-of-the-art technologies including cell-sorting and microscopy techniques for visualizing T-cell biomolecules, and genomic technologies including genome editing for evaluating detailed changes in T cells. I will thereby use primary T cells isolated from peripheral blood of healthy individuals as well as patients with reduced CTLA- 4 protein, in order to relate my findings to human disease. My study will be highly important for expanding our understanding of regulatory T-cell biological mechanisms, and provides a unique opportunity for directly assessing treatment options of T-cell driven autoimmunity through elevating the regulatory protein CTLA-4.