KIR3DS1 Directs NK Cell-mediated Control of Adenovirus and BK Polyomavirus Infection

Abstract

Human adenovirus type 5 (HAdV5) and BK polyomavirus (BKPyV) are chronic viruses that cause severe infections in immunocompromised individuals. Reactivation of HAdV5 is a major threat for patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT), while BKPyV reactivation after renal transplantation leads to the serious pathology BKPyV-associated nephropathy (BKVAN). Genetic epidemiological studies in patient cohorts consistently report associations of loci encoding for killer cell immunoglobulin-like receptors (KIRs) with protection from viral diseases. These KIRs are used by natural killer (NK) cells to recognize human leukocyte antigen class I (HLA-I) expressed on infected target cells and thus contribute to the control of viral infections. In this work, profiling of NK cell ligands on host cells infected with HAdV5 and BKPyV identified de novo induction of the non-classical HLA class I molecule HLA-F, a high affinity ligand for the activating KIR3DS1 receptor. The upregulation of HLA-F surface expression enabled recognition of HAdV5 and BKPyV host cells by KIR3DS1 and triggered activation of co-cultured KIR3DS1+ reporter and primary NK cells. KIR3DS1+ NK cells further showed enhanced cytotoxicity against HAdV5-infected intestinal epithelial cells derived from human intestinal organoids. Immunoimaging of tissue samples obtained from BKVAN patients exhibited elevated HLA-F protein levels and retrospective statistical analyses of a pediatric patient cohort revealed a protective association of the KIR3DS1+/HLA-Bw4+ compound genotype in HAdV reactivation after allo-HSCT. Considering the lack of safe antiviral medication for severe HAdV and BKPyV infections, the KIR3DS1–HLA-F immune axis constitutes a promising basis for developing effective immunotherapies.