What is Exhaustion?
Have you ever felt so exhausted that you just can’t keep going? Cells experience this too! Cellular exhaustion is a state in which cells, particularly immune cells such as T cells, lose their ability to perform their normal functions effectively. Normally, after the clearance of antigen, some T cells remain as memory T cells to preserve a memory for the specific antigen to effectively counteract the pathogen upon restimulation. Differently, following a very long battle with pathogens or cancer cells, T cells may gain a different behavior. They may be exhausted and lose their ability to fight back.
Examples of exhaustion include chronic viral infections, such as HIV and hepatitis, and non-viral infections, such as malaria. In a different case, prolonged fighting with cancer cells also results in Exhaustion. Exhausted cells typically exhibit reduced proliferation, impaired effector functions (e.g., cytokine production, killing infected or cancerous cells), and sustained expression of inhibitory receptors like PD-1, LAG-3, and TIM-3. In addition, although the glycolytic pathway fuels the energy for active T cells, exhausted T cells exhibit an impaired metabolism with glycolysis dampened, resulting in lack of energy for cells to function effectively.
Which cells exhibit this?
Cellular exhaustion is mainly attributed to immune cells, particularly T cells. Exhausted T cells are often seen during chronic infections and in tumor microenvironment. Other immune cells, such as NK cells, may also represent similar behavior.
What are its functions?
Recent studies show that exhausted cells are not inert. Instead, the immune system takes advantage of the exhausted T cells to stop destroying the whole tissue and manage the protective efforts. Through exhaustion, T cells change their epigenetics and gene expression program according to the environmental cues, which progressively become irreversible until T cells may lose effectiveness.
How is it regulated?
Cellular exhaustion is tightly regulated by both intrinsic and extrinsic factors.
1. Intrinsic factors: Upregulation of inhibitory receptors, changes in metabolic pathways (e.g., glycolysis and mitochondrial dysfunction), and epigenetic modifications contribute to the establishment and maintenance of exhaustion.
2. Extrinsic factors: The microenvironment plays a crucial role, with chronic antigen exposure, cytokines like IL-10 and TGF-β, and suppressive signals from regulatory T cells and myeloid-derived suppressor cells contributing to exhaustion.
From Wherry, E John, and Makoto Kurachi. Nature reviews. Immunology (2015). doi:10.1038/nri3862
What are its clinical implications?
Understanding cellular exhaustion is critical in developing treatments for chronic infections and cancer. By targeting the mechanisms that regulate exhaustion, therapies can boost immune cells to enhance their ability to fight infections and tumors. Just as Tour de France cyclists need energy drinks to keep performing, immune checkpoint inhibitors help T cells regain function in fighting cancer and chronic infections. Therapies such as immune checkpoint inhibitors (e.g., anti-PD-1 and anti-CTLA-4 antibodies) aim to reverse exhaustion and restore immune cell function and have shown significant success in cancer immunotherapy. Conversely, promoting exhaustion may alleviate the adverse effects of autoimmunity by downregulating their destroying activity against our own cells.
Reference
Christina Hernandez Sherwood (2023), Energizing the Immune Army. Penn Medicine News, https://www.pennmedicine.org/news/publications-and-special-projects/penn-medicine-magazine/immune-health/energizing-the-immune-army
Wherry, E. J., & Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nature Reviews Immunology, 15(8), 486–499.
Schietinger, A., & Greenberg, P. D. (2014). Tolerance and exhaustion: Defining mechanisms of T cell dysfunction. Trends in Immunology, 35(2), 51–60.
Pauken, K. E., & Wherry, E. J. (2015). Overcoming T cell exhaustion in infection and cancer. Trends in Immunology, 36(4), 265–276.
Zheng, K., Zheng, X., & Yang, W. (2022). The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection. Frontiers in immunology, 13, 843242.