Regulatory immune cells in transplantation

Key Points The presence of regulatory immune cells in transplant recipients can shift the balance away from rejection and towards immune regulation. Different populations of T cells with regulatory activity have a role in promoting transplant tolerance. These populations include CD4 + regulatory T (T Reg ) cells, CD8 + T Reg cells, CD4 − CD8 − T cells, natural killer T (NKT) cells and γδ T cells. Control of allograft rejection and graft-versus-host disease (GVHD) can also be enhanced by various non-T cell leukocytes, including regulatory B cells, tolerogenic dendritic cells (DCs), regulatory macrophages, myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs). Distinct regulatory cell populations are present in the draining lymphoid tissue and in the peripheral blood. These cells migrate to the allograft, where they modulate immune responses by inhibiting effector cells and by inducing other regulatory cells. Early after transplantation, MDSCs and MSCs can migrate to the site of an inflammatory response and promote the development of tolerogenic DCs and macrophages that induce peripheral T Reg cell development. Cellular therapies using T Reg cells, regulatory macrophages and MSCs are being developed for clinical application to control rejection or GVHD in transplant recipients. Establishing immune tolerance in transplant recipients is essential for promoting the long-term survival of an allograft and for preventing the development of harmful graft-versus-host responses. This Review considers the clinical potential of manipulating different immunosuppressive cell populations, including regulatory T cells, B cells and macrophages, in the setting of transplantation. Immune regulation is fundamental to any immune response to ensure that it is appropriate for the perceived threat to the host. Following cell and organ transplantation, it is essential to control both the innate immune response triggered by the injured tissue and the adaptive immune response stimulated by mismatched donor and recipient histocompatibility antigens to enable the transplant to survive and function. Here, we discuss the leukocyte populations that can promote immune tolerance after cell or solid-organ transplantation. Such populations include regulatory T cells, B cells and macrophages, as well as myeloid-derived suppressor cells, dendritic cells and mesenchymal stromal cells. We consider the potential of these regulatory immune cells to develop and function in tr