CD8 T Cell Sensing of Type I Interferon Impacts Anergy

Peripheral tolerance is indispensable for the maintenance of immune homeostasis, allowing protective immunity while limiting responses to self-antigens. CD8 T cells activated in the absence of co-stimulation and pro-inflammatory cytokines are either deleted, rendered anergic, or actively suppressed. These mechanisms are well established, but the cues determining the mode and depth of peripheral tolerance remain incompletely understood. Here, we identify type I interferon (IFN-I) signalling in T cells as a key modulator of peripheral tolerance in the absence of infection. In the complete absence of IFN-I signalling, autoreactive CD8 T cells are rendered anergic, and their expansion, phenotype and function are tightly controlled. Basal levels of IFN-I are sufficient for self-reactive CD8 T cells to expand and retain partial effector functions in the absence of viral infections. This is dependent on T cell-intrinsic IFN-I sensing and is associated with the generation of a partially anergic, TCF1⁺ CD8 T cell subset that can contribute to a pathogen-specific immune response. Collectively, our results suggest that elevated basal IFN-I levels limit anergy induction, providing a potential mechanistic explanation for the association of baseline inflammation with the development of autoimmunity.