Human genetic defects impairing lymphocyte cytotoxicity: causes and consequences

Project Summary

The project will investigate molecular mechanisms of impaired lymphocyte cytotoxicity through the study of patients with the severe immunopathology of familial haemophagocytic lymphohistiocytosis (HLH). A degranulation defect observed in a patient with a mutation in a new gene associated with HLH opens the possibility to uncover a previously unknown link between the transport of recycling endosomes and the lytic granule exocytosis pathway. Moreover, A01 will explore the basis of rubella vaccine virus induced granulomas, an unexpectedly observed immunopathology in a fraction of patients with cytotoxicity defects. The study of patients will be combined with a skin virus infection model to follow the hypothesis that proteins of the degranulation machinery are linked to virus control in the skin by mediating so far unknown immune functions different from cytotoxicity.