ADAMs going viral: novel regulators of dendritic cell function during viral infection

• Applicant: Ronald Backer, Ph.D.
• Subject Area: Immunology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391651816

Dendritic cells (DC) are crucial initiators of effective immune responses against viruses. Upon infection, DC mature into potent antigen-presenting cells with the ability to prime naïve T cells and initiate adaptive immune responses, but DC also activate innate immune cells such as natural killer cells. Although the importance of gene transcription and translation of inflammatory proteins has been extensively studied, many molecular cues, in particular, the role of post-translational modification of cell-surface molecules in controlling DC function are essentially unknown. A disintegrin and metalloproteinase (ADAM) family members ADAM10 and ADAM17 play a crucial role in the shedding of cell membrane-associated substrates. This so called ectodomain shedding results in the shedding of a diversity of cytokines and adhesion molecules and thereby regulates the activity, localization and interaction of many different cell types. However, the exact function of ADAM10 and ADAM17 in DC and resulting immunity remain elusive.Strikingly, my preliminary data demonstrate that post-translational shedding by ADAM10 and ADAM17 is a novel unexplored mechanism controlling DC function, as viral infection of mice with ADAM10- and ADAM17-deficient DC led to stronger pro-inflammatory responses as well as superior anti-viral T cell responses controlling viral replication in vivo. Therefore, I hypothesize that ADAM10- and ADAM17-mediated ectodomain shedding on DC acts as a post-translational molecular switch that governs critical aspects of DC biology, and as such, plays a crucial role in the induction and regulation of anti-viral immune responses. Taking advantage of unique CD11c-specific ADAM10 and ADAM17 knockout mice, in combination with innovative secretome and transcriptome analysis, I will identify novel substrates of ADAM10 and ADAM17 that are involved in DC immune regulation. Moreover, using state-of-the-art analysis of in vivo infection models molecularly define how ADAM10- and ADAM17-mediated ectodomain-shedding on DC is involved in the induction and regulation of anti-viral immune responses. This research proposal will uncover the importance of post-translational modification by ADAMs as a novel crucial pathway to initiate and control immunity, and as such will open a completely new field of research in DC biology. In the long term, this will enable the development of improved DC-based therapy approaches.

• DFG Programme: Research Grants