Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
Maria E. Joosse, Fabienne Charbit‐Henrion, Remy Boisgard, Rolien C. Raatgeep, Dicky J. Lindenbergh-Kortleve, L M M Costes, Sandrine Nugteren, Nicolas Guégan, Marianna Parlato, Sharon Veenbergen, Valérie Malan, Jan Krzysztof Nowak, Iris H.I.M. Hollink, M. Luisa Mearin, Johanna C. Escher, Nadine Cerf–Bensussan, Janneke N. Samsom
Abstract
Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3 + , and Foxp3 neg CD4 + T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4 + T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4 + T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.