The NINJA mouse: a novel model to study tissue-specific peripheral T cell tolerance

Abstract

Abstract T cell inhibitory pathways induce peripheral tolerance and have evolved to avoid pathogenic autoimmunity. Generally, peripheral tolerance either prevents T cell activation or inhibits T cells during chronic responses, but it is not clear whether these functions are orchestrated by the same mechanisms. Moreover, it is not known if these mechanisms have a tissue-specific usage. Persistent viral infections and cancer leverage the T cell inhibitory pathways involved in peripheral tolerance, thus providing translational relevance to the role of these pathways in disease. However, many of the mechanisms of peripheral tolerance remain understudied, in part because few animal models can distinguish these mechanisms from those driving central tolerance. We have generated a novel mouse model (iNversion INduced Joined neoAntigen, NINJA) that bypasses central and peripheral tolerance by using genetic recombination to create a neoantigen-coding gene for de novo neoantigen expression in any tissue of choice. NINJA expresses LCMV-derived GP33–41 and GP61–80 after induction, enabling investigation of tolerance using well established immunologic tools. Prior to recombination, NINJA mice respond robustly to LCMV-Arm infection, indicating absence of tolerance. However, after recombination, LCMV GP-specific responses are significantly impaired, although mice retain the capacity of developing immunity against unrelated LCMV epitopes. PD-1 is upregulated by tolerized endogenous GP33–41-specific CD8+ T cells after hepatocyte-specific NINJA activation, thus suggesting its involvement in hepatic peripheral tolerance. We therefore propose NINJA as a model to investigate tissue-specific mechanisms of peripheral T cell tolerance.