Immune-surveillance through exhausted effector T-cells

•The phenomenon of T-cell exhaustion limits immune responses to persisting infections.•Nonetheless, these T-cells retain a certain level of function.•We review evidence that these T-cells mediate a form of immune-surveillance.•Chances and limits linked to using 'exhausted' T-cells for therapies are discussed.

Pathogens such as the human immunodeficiency virus (HIV), the hepatitis B and C virus (HBV, HCV) and certain strains of the rodent lymphocytic choriomeningitis virus (LCMV) establish a state of persisting viral replication. This occurs besides strong adoptive immune responses and the induction of large numbers of activated pathogen-specific T-cells. The failure of the immune system to clear these viruses is typically attributed to a loss of effector T-cell function - a phenomenon referred to as T-cell exhaustion. Though largely accepted, this loss of function concept is being more and more challenged by comprehensive clinical and experimental observations which highlight that T-cells in chronic infections are more functional than previously considered. Here, we highlight examples that demonstrate that such T-cells mediate a profound form of immune-surveillance. We also briefly discuss the opportunities and limitations of employing 'exhausted' T-cells for therapeutic purposes.