Intergenic risk variant rs56258221 skews the fate of naive CD4(+) T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis

Autor/innen

  • T. Poch
  • J. Bahn
  • C. Casar
  • J. Krause
  • I. Evangelakos
  • H. Gilladi
  • L.K. Kunzmann
  • A. Laschtowitz
  • N. Iuso
  • A.M. Schäfer
  • L.A. Liebig
  • S. Steinmann
  • M. Sebode
  • T. Folseraas
  • L.K. Engesæter
  • T.H. Karlsen
  • A. Franke
  • N. Hubner
  • C. Schlein
  • E. Galun
  • S. Huber
  • A.W. Lohse
  • N. Gagliani
  • D. Schwinge
  • C. Schramm

Journal

  • Cell Reports Medicine

Quellenangabe

  • Cell Rep Med 5 (7): 101620

Zusammenfassung

  • Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4(+) T (CD4(+) T(N) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4(+) T(N) is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.


DOI

doi:10.1016/j.xcrm.2024.101620