Potter, Sarah J.Zhang, LiKotliar, MichaelWu, YuehongSchafer, CaitlinStefan, KurtisBoukas, LeandrosQu’d, DimaBodamer, OlafSimpson, Brittany N.Barski, ArtemLindsley, Andrew W.Björnsson, Hans Tómas2025-11-202025-11-202024-05-03Potter, S J, Zhang, L, Kotliar, M, Wu, Y, Schafer, C, Stefan, K, Boukas, L, Qu’d, D, Bodamer, O, Simpson, B N, Barski, A, Lindsley, A W & Björnsson, H T 2024, 'KMT2D regulates activation, localization, and integrin expression by T-cells', Frontiers in Immunology, vol. 15, 1341745, pp. 1341745. https://doi.org/10.3389/fimmu.2024.13417451664-3224223202174cf316a08-2202-4fb7-844f-39d3d5ba9ff28519347179438765012https://hdl.handle.net/20.500.11815/7555Publisher Copyright: Copyright © 2024 Potter, Zhang, Kotliar, Wu, Schafer, Stefan, Boukas, Qu’d, Bodamer, Simpson, Barski, Lindsley and Bjornsson.Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D’s influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.2061173661341745eninfo:eu-repo/semantics/openAccessintegrin switchingItgalItgb7Kabuki syndrome (KS)KS1-associated immune deficiency (KSAID)recent thymic emigrant (RTE)thymocyteHematologic DiseasesHumansIntegrins/metabolismHistone-Lysine N-Methyltransferase/geneticsLymphocyte Activation/geneticsNeoplasm Proteins/geneticsT-Lymphocytes/immunologySignal TransductionMice, Inbred C57BLFace/abnormalitiesGene Expression RegulationAbnormalities, MultipleMice, KnockoutAnimalsDNA-Binding Proteins/geneticsVestibular Diseases/geneticsMyeloid-Lymphoid Leukemia ProteinMiceImmunology and AllergyImmunology/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.3389/fimmu.2024.1341745