A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis
Xiaojun Jiang, Annika Bergquist, Britt-Sabina Löscher, Geetha Venkatesh, Jeff E. Mold, Kristian Holm, Jon K. Laerdahl, Sigrid S. Skånland, Kimia T. Maleki, Martin Cornillet, Kjetil Taskén, André Franke, Tom H. Karlsen, Niklas K. Björkström, Espen Melum
Abstract
, encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon-γ (IFN-γ) production after stimulation. Homologous mutation knock-in mice developed similar IFN-γ impairment in T cells and were more prone to develop severe cholangitis when exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Transfer of wild-type T cells to knock-in mice before and during DDC exposure attenuated cholangitis. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects. Our findings suggest a protective role for T cells in PSC that might be used therapeutically.