Macrophage-derived IL-27 sustains autoreactive CD8 + cytotoxic T cells in autoimmune hepatitis.

Chronic or persistent T cell activation is widely thought to culminate in T cell exhaustion, yet how autoreactive CD8⁺ T cells remain functionally intact despite sustained self-antigen exposure is poorly understood. In chronic infection and cancer this durability is attributed to stem-like, TCF1⁺ PD-1⁺ progenitor-exhausted (Tpex) cells that reside in lymphoid tissue and continuously replenish functional effectors; whether such a reservoir operates within a chronically inflamed peripheral organ during sterile autoimmunity is unknown. Here we show that mice lacking the lysosomal nuclease DNase2a together with the type I interferon receptor Ifnar1 ( Dnase2a⁻/⁻Ifnar1⁻/⁻ ) develop spontaneous, progressive hepatic inflammation. This hepatitis was dependent on the endosomal DNA sensor TLR9, identifying self-DNA as the initiating ligand. Inflammation was marked by expansion of inflammatory macrophages and accumulation of CD8⁺ T cells co-expressing PD-1 and TOX that retained, rather than lost, effector function. Paired single-cell TCR and transcriptomic analysis revealed progenitor-exhausted T cells within the liver itself that shared clonotypes with clonally expanded PD-1 + TOX + T cells, defining a locally operating progenitor-to-effector pipeline. Spatial transcriptomics positioned these intrahepatic T cell clusters adjacent to IL-27-expressing inflammatory macrophages, and disruption of IL-27 or its receptor in bone marrow-derived cells reduced PD-1⁺ CD8⁺ T cells and their effector functions. These findings define a novel mechanism for sustaining autoreactive T cells in the liver via TLR9-driven macrophage-induced IL-27 circuit that sustains a functional, self-renewing autoreactive PD1 + CD8⁺ T cell program in situ.