Macrophage-derived IL-27 sustains autoreactive CD8+ cytotoxic T cells in autoimmune hepatitis
- 1Umass Chan Medical School
Abstract
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 PD-1+ CD8+ T cell program in situ.
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BibTeX
@misc{hao2026macrophagederived,
title = {{Macrophage-derived IL-27 sustains autoreactive CD8+ cytotoxic T cells in autoimmune hepatitis}},
author = {K. Hao and S. G. Baptista and A. S. V. Beaumond and D. M. Schafer and P. L. Kaja and K. Chiang and K. M. Gao and K. Nundel and S. V. Kumar and M. S. Sherman and A. Marshak-Rothstein and S. K. Varanasi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754422},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754422v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Macrophage-derived IL-27 sustains autoreactive CD8+ cytotoxic T cells in autoimmune hepatitis
AU - K. Hao
AU - S. G. Baptista
AU - A. S. V. Beaumond
AU - D. M. Schafer
AU - P. L. Kaja
AU - K. Chiang
AU - K. M. Gao
AU - K. Nundel
AU - S. V. Kumar
AU - M. S. Sherman
AU - A. Marshak-Rothstein
AU - S. K. Varanasi
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754422
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754422v1
AB - 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 PD-1+ CD8+ T cell program in situ.
ER -