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.
Highlights
Failure to maintain self-tolerance leads to autoreactive T cells that recognize systemic or organ-specific self-antigens and subsequently, the development of autoimmunity [1]
Mechanisms that result in decreased regulatory T cell (Treg) numbers and/or function could be contributing to self-tolerance failure
Further characterization of mt-Nd2a, an allelic variant of mtNd2, exhibited a reduction in reactive oxygen species (ROS) generated from complex I [67]. These findings demonstrate that single nucleotide polymorphism (SNP) in Mitochondrial DNA (mtDNA) can modulate disease by altering oxidative phosphorylation (OxPhos)
Summary
Failure to maintain self-tolerance leads to autoreactive T cells that recognize systemic or organ-specific self-antigens and subsequently, the development of autoimmunity [1]. Re-establishing self-tolerance by increasing Treg cell numbers and/or increasing Treg immune suppression function may inhibit autoreactive T cell effector responses and delay the progression of T cell-mediated autoimmune diseases [4]. Immunometabolic pathways of interest includes glycolysis, oxidative phosphorylation (OxPhos), and the contribution of mitochondrial-derived reactive oxygen species (mtROS) to mediate autoreactive T cell activation and differentiation by functioning as signaling molecules [7, 15, 16].
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