Lab demonstrates key molecular factor in exhaustion of immune cells—with treatment implications

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 team posited that epigenetic regulators had a major role in preventing excessive decline in the effectiveness of the exhausted cells. They thus focused on one of the most common 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 essential 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 the 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.

This latest paper lengthens a growing body of research from the Xue Lab which aims at better understanding, and arming, the immune system against viruses and cancers and other threats. Last year they published a paper in Nature Immunology that focused on the transducin-like enhancer (Tle) family of proteins.

Specifically, their inquiry homed in on Tle3, and how it exactly functions in the training of T cells. That paper followed a series of other central memory T cell publications which were also published in Nature Immunology, the Proceedings of the National Academy of Sciences, and other major journals.

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