In a study of fingertip regeneration, a team led by JAX Senior Research Scientist James Godwin found that some immune cells in mice can attack and kill cells needed to rebuild bone, while a subset of those same immune cells can protect the bone-making cells and allow regeneration to continue.
The work highlights how the delicate but crucial interplay of immune cells shapes the body's ability to replace damaged or lost tissue with new, healthy tissue. Newly published in npj Regenerative Medicine , it could also help explain why people heal differently after injury and point to potential therapies for improving tissue regeneration.
"We thought regeneration was capped, that there was a limit to how much was possible in mice and humans, but what this paper reveals is that there may be more regenerative potential than we thought," said Godwin, who is also an assistant professor at the MDI Biological Laboratory in Bar Harbor, Maine.
Like humans, mice have a limited ability to regenerate multiple types of tissue at the tips of their digits after an injury, including bone, skin, and nail. The process provides a useful model for understanding mammalian tissue repair, Godwin said.
His team wanted to understand the role of adaptive immune cells, which learn to recognize specific threats such as viruses and cancer cells, in fingertip regeneration. The work builds on his previous findings that another type of immune cell called macrophages are essential for heart regeneration in axolotls—salamanders capable of regrowing lost limbs and other tissues.
"There's always been a bit of an underappreciation of how important the immune system is in directing these repair processes, but there is a lot of accumulating evidence that this is what really determines the success or failure of most wounds," Godwin said.
Immune checks and balances
The team used 16 genetically diverse types of mice, including some lacking different types of immune cells. Regeneration was faster and more effective when adaptive immune cells were absent.
The researchers discovered that CD4+ T cells, sometimes called "helper" T cells because they coordinate immune responses, strongly inhibited regeneration. Further experiments showed that these cells could kill progenitor cells, immature cells that give rise to the specialized cells needed to rebuild bone. The team identified an immune signaling molecule called interferon-gamma as a major driver of this "cytotoxic" activity. When CD4+ T cells could not produce interferon-gamma, they no longer blocked regeneration.
"CD4+ T cells are negative forces in this context, but they're also the guardians of our body in terms of cancer and viruses," Godwin explained. "It's possible that because our human body has evolved to balance the ability to repair and the ability to ward off these threats, that we've landed in this situation where we don't have a lot of regenerative capacity, but we have good cancer and viral surveillance."
However, not all CD4+ T cells had the same effect. Regulatory T cells, a subset also called "Tregs" that normally keeps immune responses under control, protected the cells involved in rebuilding the fingertip from attack by other CD4+ T cells. Without Tregs, regeneration was delayed and the immune system began damaging uninjured bone. Adding Tregs restored regeneration, as did increasing levels of RANKL, a naturally occurring molecule that helps control bone breakdown and remodeling. The findings offer key insights into how the immune system interacts with bone and how that balance may be disrupted by disease and aging, Godwin said.
Although more work is needed to determine whether similar mechanisms occur in human tissue, the findings could inform research into stem cell and progenitor cell therapies for severe injuries. Because transplanted cells can struggle to survive, protecting them from destructive immune responses could complement efforts to deliver or activate them in the first place.
"In the future, if somebody had an injured spinal cord or major damage to one of their bones, we might be able to use targeted immunotherapy to temporarily shift the immune system and ramp up the cells that support regeneration while suppressing those that interfere with it," Godwin said. "We don't have a therapy ready, and we're not ready to go into a patient, but identifying what needs to change is an essential step toward getting there."
Citation: Beal, Z., Reeve, R.E., Hammond, E., Rosenthal, N., Godwin, J., T-regulatory cell protection of progenitor cells from CD4+ T-cell-mediated cytotoxicity is essential for endogenous mouse digit-tip regeneration. npj Regenerative Medicine (2026). DOI: 10.1038/s41536-026-00507-5
