journal.pgen.1005645.PDF (7.87 MB)
DNA repair cofactors ATMIN and NBS1 are required to suppress T cell activation
journal contributionposted on 2020-09-04, 12:15 authored by Jana Prochazkova, Shinya Sakaguchi, Michel Owusu, Abdelghani Mazouzi, Marc Wiedner, Georgia Velimezi, Martin Moder, Gleb Turchinovich, Anastasiya Hladik, Elisabeth Gurnhofer, Adrian Hayday, Axel Behrens, Sylvia Knapp, Lukas Kenner, Wilfried Ellmeier, Joanna I Loizou
Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ) in T cells is much less clear, and whether ATMIN and NBS1 function in synergy in T cells is unknown. Here, we investigate the roles of ATMIN and NBS1, either alone or in combination, using murine models. We show loss of NBS1 led to a developmental block at the double-positive stage of T cell development, as well as reduced TCRα recombination, that was unexpectedly neither exacerbated nor alleviated by concomitant loss of ATMIN. In contrast, loss of both ATMIN and NBS1 enhanced DNA damage that drove spontaneous peripheral T cell hyperactivation, proliferation as well as excessive production of proinflammatory cytokines and chemokines, leading to a highly inflammatory environment. Intriguingly, the disease causing T cells were largely proficient for both ATMIN and NBS1. In vivo this resulted in severe intestinal inflammation, colitis and premature death. Our findings reveal a novel model for an intestinal bowel disease phenotype that occurs upon combined loss of the DNA repair cofactors ATMIN and NBS1.
AnimalsCell Cycle ProteinsColitisDNA DamageDNA RepairDNA-Binding ProteinsImmunophenotypingLymphocyte ActivationMiceNuclear ProteinsReactive Oxygen SpeciesReceptors, Antigen, T-Cell, alpha-betaRecombination, GeneticSpleenT-LymphocytesTranscription FactorsBehrensHaydayDevelopmental Biology0604 Genetics