In 1995, Sakaguchi et al. first discovered Treg cells in the study of autoimmune diseases in mice [
12]. Since then, Treg cells have become a hotspot of research on autoimmune diseases, tumours and other diseases. Treg cells mature in the thymus. Interleukin-2 (IL-2) plays an important role in the survival and development of Treg cells. Foxp3, a member of the forkhead box family of transcription factors, is currently recognized as a specific identification marker of Treg cells and is also an essential molecule for the development and functional expression of Treg cells [
13]. Treg cells are mainly divided into two categories: naturally occurring Treg cells (nTregs) and induced Treg cells (iTregs). nTregs exist naturally in the thymus, and iTregs are generated from naive T cells in peripheral lymphoid tissues under stimulation by self-antigens [
14]. M-CSF and RANKL, which induce the differentiation of osteoclasts are produced under the action of immune cells, bone marrow stromal cells, osteoblasts and fibroblasts [
7]. Treg cells have immunosuppressive functions. They can inhibit the production of osteoclasts by preventing the production of RANKL and M-CSF, leading to an increase in bone mass [
15]. Studies have shown that the main mechanisms through which Treg cells affect bone include cell contact-dependent mechanisms and inhibitory cytokine inhibition mechanisms [
16]. Recently, it has been pointed out that nTregs mainly inhibit the production of osteoclasts through a cell contact-dependent mechanism, while the inhibitory effect of iTregs occurs through an inhibitory cytokine-dependent mechanism [
6]. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important surface molecule involved in Treg cell-mediated cell contact-dependent inhibition of osteoclast generation [
17]. Treg cells expressing CTLA-4 bind to CD80/CD86 on the surface of osteoclast precursor cells and induce the activation of indoleamine-2,3-dioxygenase in osteoclast precursor cells. Activated indoleamine-2,3-dioxygenase can degrade tryptophan, promote the apoptosis of osteoclast precursor cells, and thus inhibit bone resorption [
18]. In addition to triggering immunosuppression through direct contact between cells, Treg cells can also secrete inhibitory cytokines that have indirect immunosuppressive activity. IL-10 is one of the inhibitory cytokines secreted by Treg cells and can inhibit the proliferation of T cells and the production of cytokines by T cells. IL-10 can inhibit the differentiation and maturation of osteoclasts by upregulating the secretion of osteoprotegerin (OPG) and downregulating the expression of RANKL and M-CSF [
5,
19]. IL-35 is a newly discovered cytokine secreted by Treg cells that can reduce the expression of IL-17, thereby reducing the progression of collagen-induced arthritis in mice [
20]. It has been demonstrated that after injection of mice with Treg cells that were amplified and purified in vitro with magnetic beads and coated with anti-CD3 and anti-CD28 antibodies, the expression of cytokines inhibiting osteoclast generation, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), IL-5 and IL-10, increased significantly in the mice [
17,
21]. In addition, evidence has shown that Treg cells also have certain effects on osteoblasts [
22]. Treg cells can promote the proliferation and differentiation of osteoblasts by secreting TGF-β and activating intracellular effectors such as mitogen activated protein kinase (MAPK) and Smad-related proteins that induce mesenchymal stem cells to differentiate into osteoblasts and promote the proliferation and differentiation of these osteoblasts [
23]. In addition, on the surface of osteoblasts, there are specific receptors for each subtype of TGF-β. Binding of TGF-β to its receptor on the surface of osteoblasts can accelerate the generation of osteoblasts through the Smad protein. The Smad protein has been shown to be directly involved in TGF-β signalling pathway-induced osteoblast formation [
23,
24]. Wnt10b is an osteogenic Wnt ligand that can activate Wnt signalling in osteoblasts. Treg cells are involved in upregulation of Wnt10b by CD8
+T cells during intermittent PTH treatment and supplementation with the
probiotic Lactobacillus rhamnosus GG [
14,
25]. Recently, the CD8 counterpart of Treg cells has been discovered and is called Foxp3
+CD8
+Treg cells [
3]. These cells do not affect the survival of osteoclasts, but they can inhibit the maturation and activity of osteoclasts by suppressing the formation of their actin rings. Simultaneously, in the bone marrow, the unique property of osteoclasts to induce Foxp3
+CD8
+Treg cells and the ability of Foxp3
+CD8
+Treg cells to regulate osteoclast function establishes a bi-directional regulatory loop between these two types of cells [
26]. Interestingly, this regulatory loop does not require the presence of various pro-inflammatory cytokines [
26]. Unlike CD4
+Treg cells which are present in large numbers in peripheral blood and the lymphatic circulation (accounting for approximately 5–12% of all CD4
+T cells), CD8
+Treg cells are present in small numbers in peripheral blood and the lymphatic circulation, accounting for only 0.2–2% of total CD8
+T cells in various lymphoid organs [
27]. Thus, current studies on CD8
+Treg cells are not sufficient, and the role of CD8
+Treg cells in osteoporosis has not yet been fully illustrated. Therefore, further studies in this area are needed [
3]. However, it can be confirmed that a decrease in the number or function of CD4
+Treg cells and CD8
+Treg cells in the human body will cause an increase in bone loss and consequently lead to osteoporosis.