DOCK8 mutation disrupts helper T cell differentiation via glycolytic pathway regulation

This study, led by Dr. Panpan Jiang and collaborators at Tongji Medical College, explores the critical role of the Dedicator of Cytokinesis 8 (DOCK8) gene in the differentiation of helper T cells, which are vital for the immune response. The researchers discovered that mutations in DOCK8 significantly disrupt the glycolytic pathway, a crucial metabolic process that provides the energy necessary for the activation and proliferation of CD4+ T cells.

Using a combination of in vitro experiments and metabolic assays, the team demonstrated that DOCK8-deficient T cells exhibit impaired glucose uptake and decreased lactate production, indicating a shift away from optimal glycolytic metabolism. This metabolic alteration was directly correlated with reduced differentiation of helper T cells, which are essential for coordinating immune responses.

“Our findings reveal that DOCK8 mutations not only affect the structural functions of immune cells but also critically impair their metabolic programming,” stated Dr. Jiang. The research highlights the importance of metabolic flexibility in immune cell function and suggests that restoring glycolytic activity could enhance the immune response in individuals with DOCK8 mutations.

The study also delves into the downstream effects of disrupted glycolysis on signaling pathways that influence T cell fate decisions. By analyzing gene expression profiles, the researchers identified key transcription factors that are adversely affected by the altered metabolic state, thereby elucidating the complex interplay between metabolism and immune cell differentiation.

Given the increasing recognition of metabolic dysregulation in immune disorders, this research provides vital insights that could inform the development of targeted therapies. “By targeting metabolic pathways, we might be able to develop new treatment strategies that improve immune function in patients with DOCK8-related immunodeficiencies,” Dr. Jiang added.

These findings open new avenues for future research into therapeutic interventions aimed at enhancing immune responses in patients suffering from genetic mutations affecting DOCK8 and related pathways.

See the article: 

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells

https://onlinelibrary.wiley.com/doi/full/10.1002/mco2.747