biostudies-literaturePotter SJNIDDK NIH HHSNINDS NIH HHSNIAMS NIH HHS1341745https://www.ebi.ac.uk/biostudies/studies/S-EPMC11099208biostudies-literatureUnknown15Individuals 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 <i>Kmt2d</i> 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 <i>Kmt2d</i> 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.Frontiers in immunologyKMT2D regulates activation, localization, and integrin expression by T-cells.PMC11099208P30 DK078392R03 NS133727P30 AR070549Bjornsson HTStefan KPotter SJBarski AKotliar MZhang LSchafer CBodamer OSimpson BNLindsley AWBoukas LQu'd DWu YfalseKMT2D regulates activation, localization, and integrin expression by T-cells.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 <i>Kmt2d</i> 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 <i>Kmt2d</i> 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.2024-01-01T00:00:00Z20242026-06-01T08:06:30.509Z2026-04-08T10:51:56.832ZS-EPMC110992083876501210.3389/fimmu.2024.1341745