Prof. Dr. Stephan Ehl (CIBSS-AI), CCI Centre for Chronical Immunodeficiency (University Medical Center Freiburg, Faculty of Medicine)
Monogenetic diseases of the immune system provide unique insights into the function of the human immune system. Apart from increased susceptibility to infection, patients also frequently suffer from consequences of impaired immune regulation. Recently, germline gain-of-function STAT3 mutations have been associated with a syndrome of early-onset autoimmunity, T cell-mediated immunopathology and lymphoproliferation. We have identified more than 20 patients with STAT3 GOF associated disease, have cloned their mutations and expressed them in STAT3 deficient cell lines. The experimental characterization of these clinically relevant mutant STAT3 alleles offers a unique opportunity to understand how signalling and metabolic functions of STAT3 are integrated to determine the differentiation, function and life-span of human T cells. The cellular systems established in this project will also allow testing novel treatment approaches targeting the identified key functions of the canonical and non-canonical STAT3 pathway. Successful strategies can then be validated in primary patient cells and eventually in clinical studies.