Type III interferon-mediated effector functions of adaptive NK cells involved in control of HCMV infection

• Applicant: Professor Dr. Markus G. Uhrberg
• Subject Area: Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514891263

Natural killer (NK) cells are part of the first line of defense against acute viral infections. Recently, a novel type of virus-specific NK cell was identified that expands during acute cytomegalovirus (CMV) infection and efficiently mediates antibody-dependent cellular cytotoxicity (ADCC). In contrast to conventional NK cells, adaptive NK cells can persist for many years and thus have the potential to contribute to long-term protection against reinfection or reactivation from latency. A hallmark of these adaptive (also known as memory) NK cells is the expression of the stimulatory receptor NKG2C, which binds to human leucocyte antigen E (HLA-E). Besides the well-defined HLA-E/NKG2C axis, it is presently unclear which other factors control the activation of adaptive NK cells during viral infections. In this regard, we have acquired preliminary data showing that adaptive NK cells are uniquely responsive to type III interferons, i.e. IFN lambda (IFNl) 1-4 due to specific up-regulation of the IFNl receptor (IFNlR). Lambda IFNs are a more recently described class of IFNs with homology to the classic type I IFNs (IFNalpha/beta) but with a more focused mode of action, including front-line immune responses against virus-infected epithelial cells. The responsiveness of adaptive NK cells to IFNl is particularly relevant given the well-described low sensitivity of adaptive NK cells to other key cytokines acting on conventional NK cells, such as IL-12 and IL-18. The results of additional transcriptomic analyses suggest that exposure to IFNl initiates a highly specific virus defense program in adaptive NK cells. In the present project, we would like to thoroughly characterize how type III interferons modulate the effector functions of adaptive NK cells. We would like to understand how IFNl-mediated stimulation synergizes with coactivation via the HLA-E/NKG2C axis and will use transporter associated with antigen processing (TAP)-deficient HLA-E transfectants enabling fine-tuning of HLA-E surface expression by loading defined peptides. Second, we will use transcriptomic, proteomic, and epigenetic analyses to characterize the changes in global expression programs in IFNl-treated primary adaptive NK cells. Third, we plan to analyze how IFNl modulates the function of adaptive NK cells in an in vitro infection model based on coculture of NK cells with human cytomegalovirus (HCMV)-infected mesenchymal stem cells. Finally, we will assess the clinical relevance of IFNl-mediated stimulation of adaptive NK cells by analyzing leukemia patients experiencing HCMV reactivation following chemotherapy and hematopoietic stem cell transplantation (HSCT). Together, the proposed work is expected to lead to a better understanding of type III IFN-mediated regulation of adaptive NK cells during virus infections, which we hope will help to unleash their high translational potential in cellular therapy in the setting of clinical reactivation of HCMV.

• DFG Programme: Research Grants