A comprehensive new review examines the complex role of T cell exhaustion in organ transplantation, highlighting how this dysfunctional immune state can both promote graft tolerance and create vulnerabilities to infection and malignancy. The authors explore the molecular, epigenetic, transcriptional, and metabolic mechanisms underlying T cell exhaustion and discuss emerging strategies to intentionally induce or modulate exhaustion as a therapeutic tool in transplantation medicine.
T cell exhaustion develops when T cells experience persistent antigen stimulation over prolonged periods, such as during chronic infections, cancer, or exposure to transplanted tissues. Exhausted T cells gradually lose their ability to proliferate, produce cytokines, and eliminate target cells. This state is characterized by high expression of inhibitory receptors, extensive epigenetic remodeling, altered transcriptional programs, and profound metabolic reprogramming.
One of the defining features of exhausted T cells is the increased expression of inhibitory immune checkpoint molecules. The review focuses on four key receptors—PD-1, CTLA-4, TIM-3, and LAG-3—which suppress T cell activation and function through distinct but overlapping signaling pathways. Persistent expression of these receptors contributes to the maintenance of the exhausted phenotype and limits immune-mediated tissue damage.
The authors emphasize that T cell exhaustion is not merely a transient functional decline but is supported by stable epigenetic reprogramming. DNA methylation, histone modifications, and large-scale chromatin remodeling create a unique transcriptional landscape that distinguishes exhausted T cells from both effector and memory T cells. These epigenetic changes can persist even after antigen removal, resulting in what researchers describe as “epigenetic scarring.”
Several transcription factors play critical roles in establishing and maintaining exhaustion. Among these, TOX is identified as a master regulator that drives the expression of inhibitory receptors and exhaustion-associated genes while suppressing effector and memory T cell programs. Other important regulators include NFAT, NR4A, MYB, TCF-1, BATF, and IRF4, which collectively orchestrate the progression from progenitor exhausted cells to terminally exhausted populations.
The review also highlights substantial changes in cellular metabolism during exhaustion. While functional effector T cells rely heavily on glycolysis to support rapid proliferation and immune activity, exhausted T cells exhibit impaired glucose uptake and reduced glycolytic capacity. Instead, they become increasingly dependent on fatty acid oxidation and display mitochondrial dysfunction, diminished ATP production, and altered amino acid metabolism. These metabolic adaptations contribute directly to impaired immune function. The metabolic shifts are illustrated in figures showing reduced glycolysis and altered lipid metabolism in exhausted T cells compared with functional effector cells.
In transplantation, T cell exhaustion presents both benefits and risks. Moderate exhaustion can suppress alloreactive immune responses, reducing graft rejection and promoting long-term graft acceptance. Excessive exhaustion, however, may compromise antiviral immunity and tumor surveillance, increasing susceptibility to opportunistic infections and malignancies. The balance between these opposing effects is therefore a major clinical challenge.
The role of exhaustion varies across transplant settings. In kidney transplantation, higher levels of exhausted T cells have been associated with improved graft function and tolerance. In liver transplantation, the organ’s unique antigen-rich environment and immunosuppressive microenvironment strongly favor T cell exhaustion, contributing to the liver’s well-known tolerogenic properties. In hematopoietic stem cell transplantation, exhaustion can reduce graft-versus-host disease but may simultaneously weaken beneficial graft-versus-leukemia responses.
Several cellular populations actively promote T cell exhaustion. Regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), M2 macrophages, and natural killer cells can all contribute through direct cellular interactions and secretion of inhibitory cytokines. Among soluble mediators, TGF-β and IL-10 are particularly important drivers of exhaustion, influencing both transcriptional programs and metabolic pathways that reinforce dysfunctional T cell states.
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Reference
Yining Wang, You Wu, Yufei Shen, Yujia Chen, Yifan Zhao, Xiandong Zeng, Kang He, The multifaceted landscape of T cell exhaustion in organ transplantation: From molecular mechanisms (epigenetics, transcription, metabolism) to induction strategies, Genes & Diseases, Volume 13, Issue 5, 2026,
101965, https://doi.org/10.1016/j.gendis.2025.101965

Funding
Shanghai Natural Science Foundation (No. 23ZR1438600)
Shanghai Research Center for Organ Transplantation
Category A Key Research Center of Shanghai Municipality (No. 2022ZZ01016)
Dynamic Evolution and Regulatory Mechanisms of Host Immune Response Before and After Liver Transplantation (Joint Application A)
Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital Technology Achievement Transformation Cultivation Project (No. RJZH26-005)
Shanghai Jiao Tong University School of Medicine Science Popularization Cradle Program (No. YL250209)
Undergraduate Innovation Training Program of Shanghai Jiao Tong University School of Medicine (No. 20260006)
Shanghai Jiao Tong University School of Medicine “Young Science and Technology Innovation Workshop” (GanWeiRenXian)
Special Program of the National Natural Science Foundation of China (No. 82241221)