Redox Regulation of LAT Enhances T Cell-Mediated Inflammation.

Area of Science:

• Immunology
• Molecular Biology
• Redox Biology

Background:

• Neutrophil cytosolic factor 1 (Ncf1) gene polymorphisms are linked to autoimmune diseases, suggesting a role for reduced oxidative burst.
• Reactive oxygen species (ROS) influence T cell function, but the precise signaling pathways are not fully understood.
• The adaptor protein Linker for Activation of T cells (LAT) is crucial for T cell receptor signaling and possesses redox-sensitive cysteine residues.

Purpose of the Study:

• To investigate whether ROS regulate T cell-dependent inflammation by targeting the LAT adaptor molecule.
• To elucidate the role of specific cysteine residues (C120 and C172) in LAT's redox regulation.
• To assess the impact of redox-insensitive LAT on T cell activation and autoimmune disease models.

Main Methods:

• Generation of a mouse model with cysteine-to-serine mutations in LAT (LAT^SS).
• Analysis of LAT localization and phosphorylation in response to redox changes.
• Evaluation of T cell populations in LAT^SS mice and in combination with NCF1 mutations (NCF1^m1j).
• Assessment of T cell-dependent autoimmune inflammation using the collagen-induced arthritis (CIA) model.

Main Results:

• Redox regulation of LAT via C120 and C172 influences its cellular localization and phosphorylation.
• LAT^SS mice exhibited altered thymocyte and peripheral T cell numbers.
• Redox-insensitive LAT exacerbated T cell-dependent autoimmune inflammation in CIA.
• This exacerbation was abrogated in ROS-deficient NCF1^m1j mice, indicating NCF1-dependent ROS are involved.

Conclusions:

• LAT is a redox-regulated molecule that functions to repress T cell activation.
• ROS, generated by NCF1 in antigen-presenting cells, target LAT to modulate T cell responses.
• LAT's redox regulation is a critical mechanism controlling T cell-mediated autoimmune inflammation, offering potential therapeutic targets for rheumatoid arthritis and related conditions.