Defining the bio-molecular features of pigment cell-specific NK cell memory

• Applicant: Professor Christoph Wilhelm, Ph.D., since 3/2018
• Subject Area: Immunology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320398819

Until recently it was believed that natural killer cells (NK cells), cells of the innate immune system particularly involved in attacking virus-infected- and tumor cells, exhibited short-lived responses limited to fixed reaction-patterns. In recent years it has however become appreciated that certain NK cells possess features typical of adaptive immunity, as they can adjust their responses to the challenge they meet and also remember the specific challenge they responded to over prolonged periods of time. The latter was shown to enable so-called memory NK cell recall responses. This appeared to be true for splenic NK cell reactivity against some viruses and in particular also for hepatic NK cell responses against contact sensitizing compounds (haptens). My preliminary work on the pigment cell-specific contact sensitizer monobenzone has established that also this compound induces a memory NK cell response. I have identified its establishment to be dependent upon the lymph node homing of tissue-resident macrophages. The latter event was dependent on the monobenzone-mediated triggering of a single innate pattern recognition receptor: the NLRP3-inflammasome. In the mean time, other studies have defined NK cells, including memory NK cells, to belong to the Innate Lymphoid Cells (ILC). Still, agreement has not been reached whether hepatic memory NK cells are killer ILC or rather represent the ILC1 group. Also, it remains unclear by which molecular means memory NK cells identify their target cell and which exact antigenic determinant they recognize. The monobenzone-induced pigment cell-specific memory NK cells (MIPS memory NK cells) have the very unique feature of specifically reacting against autologous pigmented cells, including ones that have not been monobenzone-exposed. Whereas normal haptens are broad-acting, and the responsive memory NK cells are not restricted to a single cell type, the cell type-specificity of the MIPS memory NK cells for the first time allows deep investigation into an isolated memory NK cell population responsive to a single autologous cell type. In this project, I now aim to establish whether the MIPS memory NK cells specifically recognize an antigenic determinant from the melanosomal compartment and importantly define whether the MIPS memory NK cell population shares molecular determinants that sets them aside from naïve memory NK cells. Also I wish to establish the exact phenotype of MIPS memory NK cells (are they killer ILC, or rather ILC1?). This would for the first time provide insight into how such ILC can attack host tissues, a process possibly lying at the root of various autoimmune diseases. This can open new avenues of ILC-based research into unexplored aspects of autoimmune pathogenesis. Moreover, it can ignite research into distinct applications for anti-tumor immunotherapy using such auto-reactive ILC.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells
• Cooperation Partners: Professor Dr. Veit Hornung; Professor Dr. Michael Hölzel; Professor Dr. Jörg Vogel
• Ehemaliger Antragsteller: Dr. Jasper G. van den Boorn, until 2/2018