Targeting Mitochondrial-Derived Reactive Oxygen Species in T Cell-Mediated Autoimmune Diseases

Abstract

Mitochondrial dysfunction resulting in oxidative stress could be associated with tissue and cell damage common in many T cell-mediated autoimmune diseases. Autoreactive CD4 T cell effector subsets (Th1,Th17) driving these diseases require increased glycolytic metabolism to upregulate key transcription factors (TF) like T-bet and RORγt that drive differentiation and proinflammatory responses. However, research in immunometabolism has demonstrated that mitochondrial-derived reactive oxygen species (ROS) act as signaling molecules contributing to T cell fate and function. Eliminating autoreactive T cells by targeting glycolysis or ROS production is a potential strategy to inhibit autoreactive T cell activation without compromising systemic immune function. Additionally, increasing self-tolerance by promoting functional immunosuppressive CD4 T regulatory (Treg) cells is another alternative therapeutic for autoimmune disease. Tregs require increased ROS and oxidative phosphorylation (OxPhos) for Foxp3 TF expression, differentiation, and anti-inflammatory IL-10 cytokine synthesis. Decreasing glycolytic activity or increasing glutathione and superoxide dismutase antioxidant activity can also be beneficial in inhibiting cytotoxic CD8 T cell effector responses. Current treatment options for T cell-mediated autoimmune diseases such as Type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) include global immunosuppression, antibodies to deplete immune cells, and anti-cytokine therapy. While effective in diminishing autoreactive T cells, they can also compromise other immune responses resulting in increased susceptibility to other diseases and complications. The impact of mitochondrial-derived ROS and immunometabolism reprogramming in autoreactive T cell differentiation could be a potential target for T cell-mediated autoimmune diseases. Exploiting these pathways may delay autoimmune responses in T1D.

Keywords: T cell; autoimmunity; immunometabolism; mitochondria; reactive oxygen species.

Figure 1

Autoreactive Th1 and Th17 T cell responses rely on glycolysis while immunosuppressive Treg cells utilize oxidative phosphorylation (OxPhos). Th1 cells contribute to β-cell death and destruction in type 1 diabetes (T1D) and Th17 cells contribute to pathogenesis of other T-cell mediated diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Upon activation, naïve T cells will metabolically shift from OxPhos-dependence to a balance between glycolysis and OxPhos. Throughout early activation and differentiation, this balance is maintained until a commitment toward an effector function is achieved. Once fully differentiated, autoreactive Th1 and Th17 cells utilize glycolysis for homeostasis and maintenance while immunosuppressive Treg cells rely on OxPhos.

Figure 2

Stimulation of TCR and CD28 causes a metabolic shift in naïve CD4 T cells. T cell receptor (TCR) stimulation by peptide presented on major histocompatibility complex-II (MHC-II) (A) will increase calcium (Ca²⁺) entry into the cytoplasm through store operated calcium entry (SOCE) channels (B) increasing mitochondrial-derived superoxide $(O_2^{·-})$ generation (C). Oxidative phosphorylation (OxPhos) will promote interleukin (IL)-2 expression by hydrogen peroxide (H₂O₂) signaling (D). Simultaneously, CD28 will upregulate Glut1 expression on the cell membrane increasing glucose uptake shifting metabolism away from OxPhos to glycolysis to support rapid proliferation (E).

Figure 3

ROS production originates from various locations throughout the cell. Superoxide is generated within the mitochondrial matrix (A) or by membrane bound NADPH oxidases (B). Superoxide dismutase (SOD) located within the mitochondrial matrix (A), within the cytoplasm (C), or extracellularly (D) will convert superoxide into hydrogen peroxide (H₂O₂) (C). Hydrogen peroxide is able to act as signaling molecule within the cell or extracellular due to its ability to diffuse across the cell membrane (E). Glutathione (GSH), located throughout the cytoplasm, will regulate hydrogen peroxide levels by converting hydrogen peroxide into water (F).