Chronic and viral infections can literally exhaust certain key cells in the immune system from a constant barrage of attacks. But a new pair of groundbreaking papers by scientists at the Hackensack Meridian Center for Discovery and Innovation (CDI) has now pointed a way to understand how this exhaustion happens at a molecular level - and how medicine might be able to leverage this knowledge into treatments of the future.
The two papers appear back-to-back in the latest issue of the peer-reviewed journal Nature Immunology .
"Piece by piece, we are unraveling the complex interactions that tie together these immune-system responses," said Hai-Hui (Howard) Xue, M.D., Ph.D., member of the CDI, professor of Medical Sciences at the Hackensack Meridian School of Medicine, a member of Georgetown University's Lombardi Comprehensive Cancer Center, and senior author on both papers. "We believe we are on track to understand this fundamental process better than ever before - and hopefully save lives in the future because of it."
The two papers in the journal complement each other's findings.
The first, "Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate," demonstrates how the critical immune system responders called T cells enter a dysfunctional or exhausted state due to the persistence of certain viruses or cancers. Using preclinical models, the team showed through rigorous testing that the fate of success or exhaustion was determined early on by the cells' success (or lack thereof) in forming hubs of chromatin, webs of interlocked DNA and proteins, which help genetic programming to boost immune regulations. Key to this process are regulators known as Id2 and Id3 proteins which critically stabilize responses and longevity of the immune support structures by regulating their structure and maintenance.
The second paper, entitled "Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers," delves further into the ramifications of the first. By zooming in on a protein known as the CCCTC-binding factor, more commonly known by the abbreviation CTCF, the team demonstrated it to be an essential genome organizer that helps strategically insulate and alternately bind the most effective ways to respond and battle pathogen threats. In preclinical models, the scientists explored and documented how immune responses were longer-lasting and more effective with the CTCF - and suffered greatly when it was removed from the immune equation. The CTCF thus works in concert with Id2 and Id3 to keep the system healthy and running; when any piece is removed or "exhausted," it cannot effectively fight the enemy pathogen.
The papers were authored with colleagues from The George Washington University, the Zhongshan School of Medicine, the University of Iowa, and the New Jersey Veterans Affairs Health Care System.
Xue has published his investigations into T cell immunology frequently since he joined the CDI and HMH in 2020, including five senior-authored papers in Nature Immunology. He also publishes prolifically in other journals; two examples are a paper in the Proceedings of the National Academy of Sciences in December 2023 , focusing on CTCF in preparing memory T cells for pathogen re-encounter , and a study in Science Immunology showing two protein "transcription factors" called Tcf1 and Lef1 are critical modulators that direct bone marrow stem cells to the T cell path in the thymus.
