SATB1-dependent mitochondrial ROS production controls TCR signaling in CD4 T cells.

Taku Kuwabara,Terumi Kohwi-Shigematsu,Fumio Ishikawa,Yuriko Tanaka,Tomomi Ide,Motonari Kondo,Masataka Ikeda

doi:10.26508/lsa.202101093

Abstract

Special AT-rich sequence binding protein-1 (SATB1) is localized to the nucleus and remodels chromatin structure in T cells. SATB1-deficient CD4 T cells cannot respond to TCR stimulation; however, the cause of this unresponsiveness is to be clarified. Here, we demonstrate that SATB1 is indispensable to proper mitochondrial functioning and necessary for the activation of signal cascades via the TCR in CD4 T cells. Naïve SATB1-deficient CD4 T cells contain fewer mitochondria than WT T cells, as the former do not express mitochondrial transcription factor A (TFAM). Impaired mitochondrial function in SATB1-deficient T cells subverts mitochondrial ROS production and SHP-1 inactivation by constitutive oxidization. Ectopic TFAM expression increases mitochondrial mass and mitochondrial ROS production and rescues defects in the antigen-specific response in the SATB1-deficient T cells. Thus, SATB1 is vital for maintaining mitochondrial mass and function by regulating TFAM expression, which is necessary for TCR signaling.

Highlights

T-cell activation is triggered by signals via the TCR upon recognition of the complex composed with antigen peptides and self-MHC (Nel, 2002; Nel & Slaughter, 2002; Smith-Garvin et al, 2009)
We demonstrated that SATB1cKO T cells failed to express TFAM, maintain the mitochondria, and respond to TCR stimuli
Enforced TFAM expression rescued the activation capability of SATB1deficient T cells in response to TCR stimuli, indicating that lack of TFAM expression, which leads to loss of mitochondria contents, is largely responsible for T-cell dysfunction in SATB1cKO mice

Summary

Introduction

T-cell activation is triggered by signals via the TCR upon recognition of the complex composed with antigen peptides and self-MHC (Nel, 2002; Nel & Slaughter, 2002; Smith-Garvin et al, 2009). Lymphocyte-specific protein tyrosine kinase (Lck), an Src family tyrosine kinase, initiates downstream TCR signaling by phosphorylating the immunoreceptor tyrosine-based activation motif (ITAM) within the TCR-associated CD3ζ chains (Molina et al, 1992; Straus & Weiss, 1992). Lck phosphorylates ZAP70, which propagates signaling events such as intracellular calcium influx and the MAPK kinase known as Ras-MAPK or extracellular signal-regulated kinase (ERK) (van Leeuwen & Samelson, 1999). Both of these events are necessary for T-cell activation (Smith-Garvin et al, 2009; Courtney et al, 2018; Gaud et al, 2018). Regulation of Lck activity is critical for T-cell function

Methods

Results

Conclusion