A recent review published on Aug. 7 examines the role of T cell exhaustion in organ transplantation, focusing on how this immune state can promote graft tolerance while also increasing vulnerability to infection and malignancy. The authors analyze the molecular, epigenetic, transcriptional, and metabolic mechanisms underlying T cell exhaustion and discuss potential strategies to induce or modulate this process for therapeutic purposes.
T cell exhaustion arises when T cells are exposed to persistent antigen stimulation over extended periods, such as during chronic infections, cancer, or after exposure to transplanted tissues. Exhausted T cells gradually lose their ability to proliferate, produce cytokines, and eliminate target cells. This condition is marked by high expression of inhibitory receptors—specifically PD-1, CTLA-4, TIM-3, and LAG-3—which limit immune activity through overlapping signaling pathways.
The review notes that T cell exhaustion is maintained by stable epigenetic reprogramming involving DNA methylation and histone modifications that result in a distinct transcriptional landscape. These changes can persist even after the removal of antigens due to what researchers describe as "epigenetic scarring." Several transcription factors—including TOX (identified as a master regulator), NFAT, NR4A, MYB, TCF-1, BATF, and IRF4—are highlighted for their roles in establishing and maintaining exhausted states.
Metabolic alterations are also described as central features of exhausted T cells. Unlike functional effector T cells that rely on glycolysis for rapid proliferation and immune function, exhausted cells exhibit reduced glucose uptake and glycolytic capacity but increased dependence on fatty acid oxidation. They display mitochondrial dysfunction with diminished ATP production alongside altered amino acid metabolism.
In clinical transplantation settings such as kidney or liver transplants—and hematopoietic stem cell transplantation—the balance between moderate versus excessive exhaustion determines outcomes ranging from improved graft tolerance to increased susceptibility to infections or malignancies. Regulatory populations including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), M2 macrophages, natural killer cells, and soluble mediators like TGF-β and IL-10 are cited as contributors promoting this dysfunctional state.
