Endosome Traffic, Metabolism, and Proinflammatory Signaling in Lupus T Cells

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation and metabolic disturbance, where T cells play a critical role in disease pathogenesis. This dissertation investigates the molecular mechanisms underlying T cell dysfunction in SLE, focusing on the interplay between endosomal trafficking, NAD+ metabolism, and pro-inflammatory signaling. A central focus of this work is the role of the small GTPase Rab4A, which is overexpressed in SLE T cells and drives the endosomal recycling and surface expression of key immune receptors, like CD38, an NAD+-hydrolyzing ectoenzyme. CD38 activity depletes intracellular NAD+, reducing Sirtuin-1 function, and increases acetylation and activation of STAT3. In turn, STAT3 promotes expression of the transcription factor FOXO1, which represses IL-2, a cytokine essential for regulatory T cell function and immune tolerance. Concurrently, Rab4A-CD38 signaling amplifies mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 activation, further promoting differentiation of pro-inflammatory T cell subsets. Furthermore, we show preliminary results from the open-label phase of an ongoing clinical trial assessing the impact of antioxidant N-acetylcysteine (NAC) treatment in SLE patients. NAC treatment has previously been shown to restore redox balance and improve disease severity. NAC treatment normalized mTOR activation in CD4+ and CD8+ memory T cells, reversed the expansion of TH1 and TFH subsets, and was associated with reduced disease activity and improved patient-reported outcomes. Together, these studies identify Rab4A as a key upstream driver of T cell dysregulation in SLE and reveal a novel signaling axis linking receptor trafficking, NAD+ metabolism, and mTOR activation. The results highlight therapeutic opportunities for targeting redox-sensitive pathways to restore immune balance and suppress autoimmunity in lupus. Future research and directions are proposed to expand upon these discoveries and further refine targeting of these interconnected pathways for improved disease management and clinical outcomes in SLE.

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Endosome Traffic, Metabolism, and Proinflammatory Signaling in Lupus T Cells

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