Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self-reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T cells. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity.

Department of Biomedicine University Hospital and University of Basel Basel Switzerland

Department of Biomedicine University Hospital and University of Basel Basel Switzerland Swiss Institute of Bioinformatics Basel Switzerland

Department of Clinical Research Inselspital University of Bern Bern Switzerland

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic Department of Biomedicine University Hospital and University of Basel Basel Switzerland

Swiss Vaccine Research Institute Epalinges Switzerland

Swiss Vaccine Research Institute Epalinges Switzerland Division of Animal Physiology and Immunology School of Life Sciences Weihenstephan Technical University of Munich Freising Germany

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