CD4+CD25+FOXP3+ regulatory T cells to protect against graft-versus-host disease

Allogeneic hematopoietic cell transplantation (HCT) has benefited many patients with hematological malignancies and bone marrow failure states. However, graft-versus-host disease (GVHD) and immune incompetence remain significant challenges that limit the use of allogeneic HCT to patients with life-threatening, high-risk disorders because of the significant nonrelapse mortality associated with the treatment. With a greater understanding of the pathophysiology of GVHD, it has become apparent that this disorder represents a dysregulated immune reaction resulting in immune dysfunction, further exacerbated by treatment with immunosuppressive medications and injury to lymphoid tissues where immune recovery and tolerance develop. The emergence of fundamental mechanisms of immune regulation, whose pioneers received the 2025 Nobel Prize in Physiology or Medicine, has resulted in new concepts for improving outcomes for patients and offers the hope that, with a reduction in transplant-related risk, HCT can be offered to more patients with a broader range of immune-mediated disorders. In this review, the history, preclinical studies, and successful translation of CD4+CD25+FoxP3+ regulatory T cells in the context of allogeneic HCT are discussed.