Signal integration for T cell differentiation in engineered and patient-derived T cells

Prof. Dr. Stephan Ehl (CIBSS AI), Centre for Chronic Immunodeficiency,  University Medical Center

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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. In this project we focus on patients with autoimmunity and lymphoproliferation as a consequence of activating mutations in the JAK/STAT pathway. In particular, we study a patient with a N642H mutation in STAT5B, who presented with splenomegaly, hypereosinophilia and type I diabetes in the first year of life. Interestingly, the mutation was found in all T and NK cells, but not in B cells, myeloid cells or fibroblasts. We use STAT5B N642H mutant mice in competitive bone marrow chimera experiments to address this genetic enigma. Furthermore, we study the impact of the mutation on murine and patient T cells with a focus on the molecular control of their proliferative behaviour and response to cytokines. In vitro and in vivo systems have been set up to translate our findings into specific therapeutic interventions that will eventually benefit our patient.