Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

Metabolic pathways mediate pathogenesis and offer targets for treatment in rheumatic diseases.

PURPOSE OF REVIEW: The cause of autoimmune diseases remains incompletely understood. Here, we highlight recent advances in the role of proinflammatory metabolic pathways in autoimmune disease, including treatment with antioxidants and mechanistic target of rapamycin (mTOR) inhibitors. RECENT FINDINGS: Recent studies show that mTOR pathway activation, glucose utilization, mitochondrial oxidative phosphorylation, and antioxidant defenses play critical roles in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, immune thrombocytopenia, Sjögren's syndrome, large vessel vasculitis, and systemic lupus erythematosus. mTOR activity leads to Th1 and Th17 cell proliferation, Treg depletion, plasma cell differentiation, macrophage dysfunction, and increased antibody and immune complex production, ultimately resulting in tissue inflammation. mTOR also affects the function of connective tissue cells, including fibroblast-like synoviocytes, endothelial cells, and podocytes. mTOR inhibition via rapamycin and N-acetylcysteine, and blockade of glucose utilization show clinical efficacy in both mouse models and clinical trials, such as systemic lupus erythematosus. SUMMARY: The mTOR pathway is a central regulator of growth and survival signals, integrating environmental cues to control cell proliferation and differentiation. Activation of mTOR underlies inflammatory lineage specification, and mTOR blockade-based therapies show promising efficacy in several autoimmune diseases.