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

Area of Science:

• Immunology
• Epigenetics
• Genetics

Background:

• Kabuki syndrome is associated with immunodeficiency, but the mechanisms linking KMT2D gene variants to immune alterations are unclear.
• Previous studies indicated KMT2D affects integrin expression in B-cells.

Purpose of the Study:

• To investigate the role of KMT2D in regulating integrin expression and T-cell development in murine models.
• To understand the epigenetic mechanisms underlying KMT2D's influence on T-cell function.

Main Methods:

• Utilized murine models with targeted KMT2D deletion.
• Employed high-throughput RNA-sequencing and flow cytometry to analyze T-cells.
• Performed H3K4me3 ChIP-PCR to assess KMT2D's direct control over integrin genes.

Main Results:

• Decreased expression of leukocyte-specific integrins at both transcriptional and translational levels in T-cells lacking KMT2D.
• Identified perturbations in T-cell activation, maturation, adhesion, and effector functions.
• Observed accumulation of CD8+ single-positive thymocytes and altered peripheral T-cell populations, including reduced CD4+ recent thymic emigrants.

Conclusions:

• Loss of KMT2D in T-cells recapitulates key features of Kabuki syndrome-associated immunodeficiency.
• KMT2D epigenetically regulates integrin signaling, impacting T-cell development and function.
• Findings implicate epigenetic dysregulation in the immune deficiencies seen in Kabuki syndrome.