In a recent review published in Blood Reviews, authors from King’s College London highlight the therapeutic potential and use of bone marrow (BM) regulatory T cells (Tregs) for hematopoietic cell transplantation (HCT). Tregs have been of interest for use in HCT on account of their immunosuppressive capacity, and the the authors thus present a review focusing on Treg biology, development, and heterogeneity and the therapeutic potential of BM Tregs for prevention of GVHD after HSCT.
Tregs and BM Tregs
As immunomodulators, Tregs are attractive candidates for immunotherapy for several diseases including cancer and autoimmune diseases. In the body, Tregs can be found either circulating or in tissue-specific niches, all of which have distinct phenotypes. Such Treg heterogeneity is due to different developmental trajectories, which can also be replicated in vitro (known as iTregs), presenting a potentially unlimited source of treatment material. Interestingly, different tissue=specific Treg populations will adapt to their surroundings and express specific patterns. For example, Tregs in mucosal tissue will express mTOR, whereas RORγ expression is induced by the intestinal environment, resulting in a subpopulation of intestinal Tregs.
BM Tregs constitute approximately 20–60% of the total T cell population in the BM and have both immunosuppressive and tissue maintenance roles. As a subset of CD4+CD150+FoxP3+ cells, BM Tregs express several proteins including programmed cell death protein 1 (PD-1), killer cell lectin-like receptor subfamily G, member 1 (KLRG-1), and CD44, which binds to hyaluronan and anchors BM Tregs in the marrow. Furthermore, the authors note that there are differences between murine and human BM Treg expression patterns, suggesting limitations to using murine models. Within the marrow, BM Tregs regulate hematopoiesis by secreting IL-10 and adenosine. Other critical roles include maintenance of the marrow microenvironment through regulation of HSC reactive oxygen species (ROS) signalling, regulation of energy metabolism through adenosine secretion, immunosuppression through direct contact with dendritic cells (DCs) via PD-1, and stromal cell development through IL-10.
Tregs for GVHD
One of the best potential therapeutic applications of Tregs is for the prevention of GVHD. Tregs play a crucial role in establishing immune tolerance after allogeneic HCT, and a reduction in Tregs, shifting the ratio of T effectors to Treg suppressors, can contribute to GVHD. Additionally, BM Tregs play crucial roles in preventing graft failure, promoting donor engraftment through adenosine and IL-10 signalling. Interestingly, murine studies have shown that modulation of autophagy can also promote Treg expansion and allograft tolerance after HCT. In humans, the first clinical trials using blood-derived Tregs in GVHD patients were found to reduce symptoms and the amount of immunosuppression required.
In this review, the authors make a strong argument for the use of BM Tregs for HSCT given these immunosuppressive and regenerative capacities. While murine and human data demonstrate the potential of BM Tregs for preventing transplant rejection and GVHD, additional research is required. Several key factors should be explored, Treg localization after therapeutic infusion, the source of BM Tregs for therapeutic use, and elucidation of other signalling pathways influencing Tregs in the BM microenvironment. A shift in research focus to human cell-based assays is also needed. The authors further suggest that the harvesting and culturing of iTregs could allow the inclusion of Tregs in new HCT therapies.
Ashman J, Mutsonziwa N, Romano M, Kordasti S, Lombardi G, Shangaris P. Regulatory T cell niche in the bone marrow, a new player in Haematopoietic stem cell transplantation [published online ahead of print, 2022 Oct 31]. Blood Rev. 2022;101030.
Tags: patient care, GVHD, transplantation, Cellular therapy, Research, graft-versus-host disease, T cells, T cell, graft-versus-host