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The ubiquitous Torque teno virus (TTV) establishes a chronically persistent infection in the human host. TTV has not been associated with any apparent disease, but, as part of the human virome, it may confer a regulatory imprint on the human immune system with as yet unclear consequences. However, so far, only few studies have characterized the TTV-specific immune responses or the overall immunological imprints by TTV. Here, we reveal that TTV infection leads to a highly exhausted TTV-specific CD8+ T-cell response, hallmarked by decreased IFN-γ production and the expression of the inhibitory NKG2A-receptor. On a functional level, we identified a panel of highly polymorphic TTV-encoded peptides that lead to an expansion of regulatory NKG2A+ natural killer, NKG2A+CD4+, and NKG2A+CD8+ T cells via the stabilization of the non-classical HLA-E molecule. Our results thus demonstrate that TTV leads to a distinct imprint on the human immune system that may further regulate overall human immune responses in infectious, autoimmune, and malignant diseases.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which infects over 90% of the adult human population worldwide. After primary infections, EBV is recurrently reactivating in most adult individuals. It is, however, unclear, why these EBV reactivations progress to EBV+ Hodgkin (EBV+HL) or non-Hodgkin lymphomas (EBV+nHL) only in a minority of EBV-infected individuals. The EBV LMP-1 protein encodes for a highly polymorphic peptide, which upregulates the immunomodulatory HLA-E in EBV-infected cells, thereby stimulating the inhibitory NKG2A-, but also the activating NKG2C-receptor on natural killer (NK) cells. Using a genetic-association approach and functional NK cell analyses, we now investigated, whether these HLA-E-restricted immune responses impact the development of EBV+HL and EBV+nHL. Therefore, we recruited a study cohort of 63 EBV+HL and EBV+nHL patients and 192 controls with confirmed EBV reactivations, but without lymphomas. Here, we demonstrate that in EBV+ lymphoma patients exclusively the high-affine LMP-1 GGDPHLPTL peptide variant-encoding EBV-strains reactivate. In EBV+HL and EBV+nHL patients, the high-expressing HLA-E*0103/0103 genetic variant was significantly overrepresented. Combined, the LMP-1 GGDPHLPTL and HLA-E*0103/0103 variants efficiently inhibited NKG2A+ NK cells, thereby facilitating the in vitro spread of EBV-infected tumor cells. In addition, EBV+HL and EBV+nHL patients, showed impaired pro-inflammatory NKG2C+ NK cell responses, which accelerated the in vitro EBV-infected tumor cells spread. In contrast, the blocking of NKG2A by monoclonal antibodies (Monalizumab) resulted in efficient control of EBV-infected tumor cell growth, especially by NKG2A+NKG2C+ NK cells. Thus, the HLA-E/LMP-1/NKG2A pathway and individual NKG2C+ NK cell responses are associated with the progression toward EBV+ lymphomas.