Cancerous and non-cancerous blood disorders that affect the development of red blood cells can be cured through allogeneic hematopoietic stem cell transplantation (allo-HSCT). The efficacy of the therapy depends on successful engraftment of the donor’s bone marrow stem cells in the recipient patient. However, donor immune cells (αβ T cells) can attack tissues in the recipient patient to cause graft-versus-host disease (GVDH), which often affects the skin, gut, and liver with serious or fatal consequences.

A key problem until now, was the lack of clarity regarding the mechanism that maintains GVDH despite the progressive loss of effector T cell function and memory potential—a phenomenon called T-cell exhaustion, that occurs due to continued exposure to antigen. A popular theory reckoned that GVDH was maintained by the continuous migration of graft-attacking T cell effectors (alloreactive T cells) from secondary lymphoid organs to affected tissues via blood.

Warren Shlomchik, MD, is director of the Hematopoietic Stem Cell Transplant and Cell Therapy program at UPMC Hillman Cancer Center and professor of medicine and immunology at the University of Pittsburgh School of Medicine.

The current study led by scientists at the University of Pittsburgh School of Medicine (UPMC), overturns the existing mechanistic model to offer strong evidence that GVDH is instead maintained primarily by donor progenitor T cells that seed affected tissues soon after transplantation, and not by the recurrent recruitment of T cells from the blood, as believed earlier. These findings were published in the Cell Press journal Immunity on January 30 in an article titled “Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells.” The study bodes well for immune-suppressing GVDH therapies that target affected tissues and resident progenitor T cells, instead of treatments that prescribe global immunosuppressants.

“This study changes the paradigm of how people think about GVHD,” said Warren Shlomchik, MD, director of the Hematopoietic Stem Cell Transplant and Cell Therapy program at UPMC Hillman Cancer Center and professor of medicine and immunology at the University of Pittsburgh School of Medicine. “It provides important mechanistic detail about what’s going on in the tissues affected by GVHD, which could ultimately inform the development of better therapeutics and lead to better outcomes for stem cell recipients.”

Thomas Höfer, PhD, is division head of the German Cancer Research Center and professor of theoretical systems biology at the University of Heidelberg.

The investigators used multiple experimental paradigms, including parabiosis of mice with GVHD— a technique that surgically combines two organisms to develop a unified physiological system. The researchers developed a system to track alloreactive T cells in the GVDH mouse model by labelling individual T cells with unique tags that enabled them to measure their  migration and replication. They tracked over 1000 alloreactive T cell clones and collaborated with co-senior author Thomas Höfer, PhD, division head of the German Cancer Research Center and professor of theoretical systems biology at the University of Heidelberg, to mathematically model and predict the presence a small set of progenitor T cells within each tissue that form the source of a sustained pool of effector T cells.

Faruk Sacirbegovic, PhD, is research assistant professor of surgery at University of Pittsburgh.

Faruk Sacirbegovic, PhD, research assistant professor of surgery at Pitt and the lead author of the study, performed a series of experiments to confirm this prediction.  This led to the identification of a sub-population of T cells that reside within tissues and express the transcription factor TCF-1. These cells preferentially divide and specialize to form alloreactive effector T cells upon transplantation and engraftment.

“This finding is strong evidence that the disease is locally maintained by T cells in each of the tissues,” explained Shlomchik. “If tissues were constantly getting T cells from circulating blood, then the frequencies of T cell flavors in each tissue should become more and more alike over time —2but we didn’t see that.”

“Progenitor T cells are long-lived in target tissues and are critical for maintaining GVHD,” said Sacirbegovic. “After the initial seeding phase, the disease is mostly sustained within the tissue itself without a lot of input from new T cells in the blood.”

Pavan Reddy, MD, director of the cancer center at the Baylor College of Medicine, said, “The study identifies a key mechanism for the sustenance of GVHD within target tissues. The mechanisms for maintenance of GVHD have heretofore not been critically studied. This study indicates that TCF1+CD39low CD4+ T cells that are derived from the donor inoculum are a major type of T cells that maintain GVHD.”

Reddy added, “It opens up interesting questions for future studies, including but not limited to, whether these cells are also generated within the tissues besides secondary lymphoid tissues and, if when targeted they will abort ongoing GVHD.” (Reddy, who was not involved in the current study, also focuses on the immunobiology GVDH. A recent study from his team identified a novel role of microbial metabolites in GVHD target tissues).

“This seminal study demonstrates that GVHD is propagated locally by tissue resident stem-like donor T cells,” said Geoffrey Hill, MD, professor at the Fred Hutchinson Cancer Center in Seattle. “Therapeutically, these data suggest that approaches to treat established GVHD that are based on approaches to modulate T cell trafficking are likely to be unsuccessful and instead need to target tissue resident T cells and/or the local niche that support them.” (Hill was not part of the current study).

Identifying this seed population of T cell progenitors gives Shlomchik and others in the field an opportunity to find ways of preventing these cells from engrafting and dividing in target tissues in allo-HSCT recipients during the phase immediately following transplantation, although Shlomchik admits, targeting tissues beyond the skin is challenging. Such targeted methods to prevent GVDH might also find application in treating other blood disorders such as sickle cell anemia and autoimmune diseases such as lupus and multiple sclerosis.

The work was funded by the National Institutes of Health, Marie Skłodowska-Curie Actions, and the Swiss National Science Foundation.

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