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.