James, J.; Coelho, A.; Lahore, G.F.; Hernandez, C.M.; Forster, F.; Malissen, B.; Holmdahl, R. Redox Regulation of LAT Enhances T Cell-Mediated Inflammation. Antioxidants2024, 13, 499.
James, J.; Coelho, A.; Lahore, G.F.; Hernandez, C.M.; Forster, F.; Malissen, B.; Holmdahl, R. Redox Regulation of LAT Enhances T Cell-Mediated Inflammation. Antioxidants 2024, 13, 499.
James, J.; Coelho, A.; Lahore, G.F.; Hernandez, C.M.; Forster, F.; Malissen, B.; Holmdahl, R. Redox Regulation of LAT Enhances T Cell-Mediated Inflammation. Antioxidants2024, 13, 499.
James, J.; Coelho, A.; Lahore, G.F.; Hernandez, C.M.; Forster, F.; Malissen, B.; Holmdahl, R. Redox Regulation of LAT Enhances T Cell-Mediated Inflammation. Antioxidants 2024, 13, 499.
Abstract
The positional cloning of single nucleotide polymorphisms (SNPs) of the neutrophil cytosolic factor 1 (Ncf1) gene, advocating that a low oxidative burst drives autoimmune disease, demands an understanding of the underlying molecular causes. A cellular target could be T cells, which have been shown to be regulated by reactive oxygen species (ROS). However, the pathways by which ROS mediate T cell signaling remain unclear. The adaptor molecule linker for activation of T cells (LAT) is essential for coupling T cell receptor-mediated antigen recognition to downstream responses, and it contains several cysteine residues that have previously been suggested to be involved in redox regulation. To address the possibility that ROS regulate T cell-dependent inflammation through LAT, we established a mouse strain with cysteine-to-serine mutations at positions 120 and 172 (LATSS). We found that redox regulation of LAT through C120 and C172 mediate its localization and phosphorylation. LATSS mice had reduced numbers of double-positive thymocytes and naïve peripheral T cells. Importantly, redox insensitivity of LAT enhanced T cell-dependent autoimmune inflammation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). This effect was reversed on an NCF1-mutated (NCF1m1j), ROS-deficient, background. Overall, our data shows that LAT is redox-regulated, acts to repress T cell activation, and is targeted by ROS induced by NCF1 in antigen-presenting cells (APCs).
Keywords
NCF1; Reactive Oxygen Species; Linker for Activation of T cells; T cell receptor signaling; Rheumatoid Arthritis
Subject
Biology and Life Sciences, Immunology and Microbiology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
