Protein Recycling and Genetic Mechanisms Offer New Paths to Reverse T-Cell Exhaustion
Two studies identify protein recycling dysfunction and transcription factors ZSCAN20/JDP2 as drivers of T-cell exhaustion, with E3 ligases and gene deactivation offering reversal pathways. A third study finds TCF1 insufficient to revert terminally exhausted T cells.
Two new studies have identified distinct mechanisms — one involving protein recycling and the other involving genetic transcription factors — that can reverse T-cell exhaustion, a state in which immune cells become dysfunctional during prolonged battles against cancer and chronic infections.
Researchers at the University of California, San Diego (UCSD) discovered that impaired protein recycling is a key driver of T-cell exhaustion. Their findings, published in Cell in a paper titled "Proteostasis sustains T-cell differentiation potential and tumor-infiltrating lymphocyte function," show that exhausted T cells lose the ability to dismantle old and damaged proteins, leading to a buildup of misfolded proteins. The scientists found that this can be reversed by restoring specific E3 ligase enzymes — NEURL3, RNF149, and WSB1 — which tag worn-out proteins for breakdown. "When we restored specific E3 ligases, the buildup cleared, and the T cells regained their function and worked better at clearing tumors," said a post-doctoral fellow and lead author on the paper. The study was conducted in mice, but the researchers indicated that similar strategies could be employed for immunotherapy treatments in human cancer. The findings may also have implications for other diseases, as a co-author noted: "We think this loss of proteostasis resembles what occurs in neurons in other protein aggregate diseases such as Parkinson's and Alzheimer's."
In a separate line of research, scientists from the Salk Institute for Biological Studies, the UNC Lineberger Comprehensive Cancer Center, and UC San Diego identified genetic mechanisms that regulate the fate of CD8 "killer" T cells. Published in Nature, the research revealed that deactivating just two specific transcription factors — ZSCAN20 and JDP2 — can rekindle the tumor-fighting capabilities of exhausted T cells. The team constructed a genetic atlas of CD8 T cell states, delineating how these cells evolve from highly active to severely impaired. By manipulating these transcription factors, the researchers demonstrated that it is feasible to restore tumor-killing abilities without compromising long-lasting immunity, challenging the notion that immune exhaustion is an inevitable consequence of prolonged immune engagement. The researchers envision using this genetic atlas to create enhanced immune cells for adoptive cell transfer (ACT) and CAR T cell therapy.
A third study, published in Nature, examined the role of the transcription factor TCF1 in T-cell exhaustion. Using a high efficiency CRISPR knock-in methodology in mouse models, researchers found that while constitutive TCF1 over-expression can increase the size of the stem-like T cell pool, TCF1 is insufficient to revert more differentiated, terminally exhausted cells back into a stem-like state. This indicates that TCF1 can slow stem-like T cell differentiation but cannot actively de-differentiate more exhausted subsets.