Poster Presentation CD1-MR1 Workshop 2025

Activated MAIT cells drive fibrosis in primary sclerosing cholangitis in a SPARC dependent manner (#105)

Florencia Gutierrez 1 , Alberto Tinahones Ruano 1 , Michelle Baez Faria 1 , Alexander Wixom 2 , Konstantinos Lazaridis 1 , Gregory Gores 1 , Adiba Azad 1
  1. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
  2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, United States

Background: Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease involving progressive fibro-inflammation of bile ducts. The primary target cells in PSC are bile duct epithelial cells, called cholangiocytes, and the primary cells that deposit collagen in liver fibrosis are hepatic stellate cells (HSC). MAIT cells have been associated with fibrosis, although their role in PSC remains poorly understood (1). IL-17C is a cytokine derived from epithelial cells which can modulate immune responses (2). SPARC (secreted protein acidic and rich in cysteine) is an extracellular matrix glycoprotein whose role in fibrosis is unexplored (3). Hypothesis: Cholangiocyte-activated MAIT cells promote fibrosis in PSC by releasing profibrogenic molecules. Results: Flow cytometry of fresh bile duct brushings from PSC patients (n=3) reveal that 30% of T cells are MAIT cells. Bulk RNA sequencing of PSC cholangiocytes reveals increased expression of IL-17C compared to normal human cholangiocyte cell lines, while immunoblotting confirmed expression of IL-17C’s cognate receptor IL-17RE on MAIT cells. Flow cytometry of human MAIT cells showed that MR1-5-OP-RU activation led to an emergence of a SPARClow population, indicative of SPARC secretion (n=12 donors, p<0.05), which was confirmed by ELISA (n=10 donors, p<0.05). IL-17C treatment augmented SPARC secretion in MR1-5-OP-RU-activated MAIT cells (n=5 donors, p<0.05). Flow cytometry of MAIT cells co-cultured with PSC cholangiocytes (vs normal cholangiocyte cell line) showed increased production of TNFα and IL-17A (examples of fibro-inflammatory molecules), and SPARC secretion (n= 3 independent experiment, p<0.05). Immunofluorescence of SPARC on human liver sections showed enhanced SPARC expression in PSC livers when compared to control (n=5 patients/group, p<0.05). Finally, primary human HSC treated SPARC show gene upregulation of collagen (n=3, p<0.05). Conclusion: Cholangiocyte-activated MAIT cells drive fibrosis in PSC by secreting SPARC, a novel profibrogenic molecule. Results of this project may potentially unveil novel therapeutic targets in PSC.

  1. Jalan-Sakrikar N, Guicciardi ME, O’Hara SP, Azad A, LaRusso NF, Gores GJ, et al. Central role for cholangiocyte pathobiology in cholestatic liver diseases. Hepatology [Internet]. 2024 Sep 9 [cited 2025 Mar 6]; Available from: https://journals.lww.com/10.1097/HEP.0000000000001093
  2. Guttman-Yassky E, Krueger JG. IL-17C: A Unique Epithelial Cytokine with Potential for Targeting across the Spectrum of Atopic Dermatitis and Psoriasis. J Invest Dermatol. 2018 Jul;138(7):1467–9.
  3. Mazzolini G, Atorrasagasti C, Onorato A, Peixoto E, Schlattjan M, Sowa JP, et al. SPARC expression is associated with hepatic injury in rodents and humans with non-alcoholic fatty liver disease. Sci Rep. 2018 Jan 15;8(1):725.