Key Enzyme Prevents Immune Cell Exhaustion

A key enzyme and its molecular pathway are critical to keeping certain immune cells active and away from “exhaustion,” according to a new study published in the Proceedings of the National Academy of Science.

The lab of Hai-Hui “Howard” Xue, Ph.D., and colleagues demonstrate in the new paper that activated CD8+ T cells can avoid an “exhausted” state by ensuring the presence of histone deacetylase (Hdac1).

The critical pathway could have implications for immune system response to viral and other threats - particularly cancer.

“Our findings suggest that Hdac1 has non-redundant roles in modulating T-cell activity, which may be explored as a therapeutic target to achieve enhanced anti-viral/tumor immunity,” write the authors.

Like much of Dr. Xue’s other work, the latest paper focuses on CD8+ T cells. These “effector” cells allow the immune system to recognize threats - and effectively combat them when they invade the body.

But if the pathogenic threats persist, these effector cells eventually enter a state of Exhaustion” which makes them less and less effective.

The scientific team posited that epigenetic regulators had a major role in preventing excessive decline of effectiveness of the exhausted cells. They thus focused on one of the commonest protein enzymes: histone deacetylase 1 (Hdac1).

The CDI scientists tested their hypothesis on Hdac1 by using animal models to show that sustained expression of  Hdac1 was critical for less exhaustion of the cells; and by proving the opposite to be true, as well.

“These analyses indicate that Hdac1 is essentially for programming (the exhausted cells’) fate… and further suggest a broader impact of Hdac1 on survival, effector and exhaustion programs in early (exhausted cells),” the authors conclude in the paper.

Leveraging such insights for further immune-system boosting would be subject to future research work. But there are current treatment implications, according to the authors.

Currently, there is a growing interest in the oncology world to use Hdac inhibitors for treatment of certain cancers, especially in conjunction with engineered chimeric antigen receptor (CAR) T cells. However, Dr. Xue and the authors caution that such Hdac inhibitors might actually adversely impact naturally-occurring, tumor-infiltrating immune cells of the body.

Reference: Hu W, Shawn Hu S, Zhu S, et al. Hdac1 as an early determinant of intermediate-exhausted CD8+ T cell fate in chronic viral infection. PNAS. 2025;122(19):e2502256122. doi: 10.1073/pnas.2502256122

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