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Introduction: Crescentic glomerulonephritis (cGN) is a severe, T cell-mediated autoimmune disorder with limited treatment options. The availability and use of various metabolites play a critical role in T cell activation and function. However, how oxidative phosphorylation and glycolysis influence T cell fate and behavior during cGN remains poorly understood, despite their central importance to disease pathogenesis. Understanding the metabolic pathways governing inflammatory T cell function may pave the way for novel therapeutic strategies.

Methods: To study T cell metabolism in autoimmune kidney disease, we employ the nephrotoxic nephritis (NTN) model. To asses immunometabolic profiles of T-cell subpopulations in a tissue-specific context on a single-cell level, we used state-of-the-art techniques such as innovative flow cytometry assays (SCENITH) and analyses of human and murine single-cell RNA sequencing (scRNAseq) data. To assess the functional role of aerobic glycolysis in T cells, we used T cell-specific knockout mice for Ldha (a key enzyme in aerobic glycolysis) and characterize their CD4+ T cells under NTN and ex vivo.

Results: Our results demonstrate that T cell activation in both humans and wild-type mice with cGN is characterized by a preferential reliance on aerobic glycolysis. Mice with a T cell-specific deletion of Ldha (CD4-Cre Ldhaflox; Ldha T-KO) develop significantly fewer glomerular crescents compared to controls. This is accompanied by a marked reduction in CD44⁺CD62L⁻ effector CD4⁺ T cells and diminished Th1 polarization. Ex vivo, CD4⁺ T cells from Ldha T-KO mice exhibit significantly impaired proliferative capacity and increased susceptibility to cell death following CD3/CD28 stimulation. Glucose tracing analyses post-activation reveal that Ldha T-KO cells exhibit deficits in de novo nucleotide biosynthesis.

Conclusion: Kidney T cells rewire their metabolism in the NTN model by favoring glycolytic activity. Inhibition of aerobic glycolysis by genetic deletion in T cells reduced morphological kidney damage and strongly impaired effector and Th1 functions in CD4+ T cells. These findings could pave the way for a new therapeutic approach in T cell-driven kidney autoimmunity.