Upregulation of the NKG2D ligand ULBP2 by JC polyomavirus infection promotes immune recognition by natural killer cells
Authors: Jost Stephanie , Ahn Jenny , Chen Sarah , Yoder Taylor , Gikundiro Kayitare Eunice , Lee Esther , Gressens Simon B. , Kroll Kyle , Craemer Melissa , Kaynor G. Campbell , Lifton Michelle , Tan C. Sabrina 
Published: June 2023

AbstractJC polyomavirus (JCPyV) establishes a chronic infection in 70-90% of the world’s population. In immunocompetent individuals, JCPyV chronic infection is asymptomatic and not associated with diseases. However, JCPyV causes progressive multifocal leukoencephalopathy (PML), a potentially fatal complication of severe immune suppression due to monoclonal antibody treatments for cancer, autoimmune diseases and transplantation, or due to uncontrolled HIV infection. There is currently no effective treatment against PML and novel immunotherapies are urgently needed to decrease the morbidity and mortality caused by JCPyV. The risk of developing PML increases with loss of immune control by JCPyV-specific T cells and antibodies. Natural killer (NK) cells play critical roles in defense against viral infections, yet NK cell contribution to the control of JCPyV infection remains largely unexplored. Here, we first compared NK and T cell responses against JCPyV VP1 peptide pools. In about 40% of healthy donors, we detected robust CD107a upregulation and IFN-γ production by NK cells, extending beyond T cell responses. Next, using a novel flow cytometry-based killing assay, we showed that co-culture of NK cells and JCPyV-infected astrocyte-derived SVG-A cells leads to a 60% reduction in infection, on average. Expression of ligands for the activating NK cell receptor NKG2D was modulated in JCPyV-infected cells, with overall enhanced expression of ULBP2. To evaluate the impact of NKG2D triggering on NK cell-mediated elimination of JCPyV-infected cells, we performed co-cultures in the presence of NKG2D blocking antibodies, which resulted in decreased NK cell degranulation. Altogether, these findings suggest NKG2D-mediated activation may play a key role in controlling JCPyV replication and may be a promising immunotherapeutic target to boost NK cell anti-JCPyV activity.Author SummaryThe human polyomavirus JC (JCPyV) infects most people for life but only causes disease in persons with a compromised immune system. In particular, JCPyV reactivation in the brain is responsible for the development of progressive multifocal leukoencephalopathy (PML). There is currently no effective treatment for PML, which is often fatal. Natural killer (NK) cells are effector cells of the innate immune system that play critical roles in defense against viral infections, yet their contribution to the control of JCPyV infection remains largely unexplored. The current study shows that NK cells can eliminate cells infected with JCPyV and that immune recognition is partly mediated by NKG2D, an activating ligand expressed on NK cells, and its binding to ULBP2, a stress-induced ligand expressed on infected cells. Our findings provide new insights into immune mechanisms involved in JCPyV immunity, and unveil opportunities to harness NK cell function in future therapeutic strategies to target JCPyV.