AUTHOR=Vietzen Hannes , Simonitsch Cara , Friedel Benjamin , Berger Sarah M. , Kühner Laura M. , Furlano Philippe L. , Florian David M. , Görzer Irene , Koblischke Maximilian , Aberle Judith H. , Puchhammer-Stöckl Elisabeth TITLE=Torque teno viruses exhaust and imprint the human immune system via the HLA-E/NKG2A axis JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1447980 DOI=10.3389/fimmu.2024.1447980 ISSN=1664-3224 ABSTRACT=

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.