NUDT1 promotes the accumulation and longevity of CD103 T cells in primary biliary cholangitis.

Background & Aims: Pyruvate dehydrogenase (PDC)-E2 specific CD8 T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8 T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8 T-cell subpopulations and investigate their immunobiology in PBC.

Methods: Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103 T cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of T cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of T cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model.

Results: Intrahepatic CD103 T (CD69CD103CD8) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103 T cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103 T cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8 T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103 T cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8 T-cell tissue-residency via the PARP1-TGFβR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103 T cell durable survival and TGFβ-Smad signaling.

Conclusions: CD103 T cells are the dominant population of PDC-E2-specific CD8 T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103 T cell accumulation and longevity represents a novel therapeutic target in PBC.

Lay Summary: Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8 T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8 T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.