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

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


Title: KMT2D regulates activation, localization, and integrin expression by T-cells
Author: Potter, Sarah J.
Zhang, Li
Kotliar, Michael
Wu, Yuehong
Schafer, Caitlin
Stefan, Kurtis
Boukas, Leandros
Qu’d, Dima
Bodamer, Olaf
Simpson, Brittany N.
... 3 more authors Show all authors
Date: 2024-05-03
Language: English
Scope: 20
Department: Faculty of Earth Sciences
Faculty of Medicine
Other departments
Series: Frontiers in Immunology; 15()
ISSN: 1664-3224
DOI: 10.3389/fimmu.2024.1341745
Subject: Lífefna- og sameindalíffræði; integrin switching; Itgal; Itgb7; Kabuki syndrome (KS); KS1-associated immune deficiency (KSAID); recent thymic emigrant (RTE); thymocyte; Hematologic Diseases; Humans; Integrins/metabolism; Histone-Lysine N-Methyltransferase/genetics; Lymphocyte Activation/genetics; Neoplasm Proteins/genetics; T-Lymphocytes/immunology; Signal Transduction; Mice, Inbred C57BL; Face/abnormalities; Gene Expression Regulation; Abnormalities, Multiple; Mice, Knockout; Animals; DNA-Binding Proteins/genetics; Vestibular Diseases/genetics; Myeloid-Lymphoid Leukemia Protein; Mice; Immunology and Allergy; Immunology
URI: https://hdl.handle.net/20.500.11815/4941

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Citation:

Potter , 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.2024.1341745

Abstract:

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.

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Publisher Copyright: Copyright © 2024 Potter, Zhang, Kotliar, Wu, Schafer, Stefan, Boukas, Qu’d, Bodamer, Simpson, Barski, Lindsley and Bjornsson.

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