Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells

Author:

Jost Priska1,Klein Franziska1,Brand Benjamin2,Wahl Vanessa3ORCID,Wyatt Amanda3ORCID,Yildiz Daniela3,Boehm Ulrich3,Niemeyer Barbara A.1ORCID,Vaeth Martin2,Alansary Dalia1ORCID

Affiliation:

1. Molecular Biophysics, Saarland University, 66421 Homburg, Germany

2. Würzburg Institute of Systems Immunology, Max Planck Research Group at Julius-Maximilians University of Würzburg, 97078 Würzburg, Germany

3. Experimental Pharmacology, Center for Molecular Signaling (PZMS), School of Medicine, Saarland University, 66421 Homburg, Germany

Abstract

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca2+ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca2+ uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca2+ uptake. Recently, MCU has been shown to modulate Ca2+ signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that ‘chronic’ loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca2+ uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs.

Funder

Saarland University (Homfor2022) to D.A. and German Research Foundation

GZ Inst

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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