KMT2D regulates activation, localization, and integrin expression by T-cells

• Published in: Frontiers in immunology Vol. 15; p. 1341745
• Main Authors: Potter, Sarah J, Zhang, Li, Kotliar, Michael, Wu, Yuehong, Schafer, Caitlin, Stefan, Kurtis, Boukas, Leandros, Qu'd, Dima, Bodamer, Olaf, Simpson, Brittany N, Barski, Artem, Lindsley, Andrew W, Bjornsson, Hans T
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 03.05.2024
• Subjects: Abnormalities, Multiple; Animals; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Face - abnormalities; Gene Expression Regulation - genetics; Hematologic Diseases; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; Immunology; Integrins - genetics; Integrins - metabolism; Itgal; Itgb7; Kabuki syndrome (KS); KS1-associated immune deficiency (KSAID); Lymphocyte Activation - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Neoplasm Proteins - metabolism; recent thymic emigrant (RTE); Signal Transduction; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; thymocyte; Vestibular Diseases - genetics; Vestibular Diseases - immunology; Vestibular Diseases - metabolism; Kabuki syndrome (KS); recent thymic emigrant (RTE); thymocyte; Itgb7; integrin switching; Itgal; KS1-associated immune deficiency (KSAID)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1341745

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 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 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.