Regulatory network of CD8+CD28- Tregs. CD8+CD28- Tregs possess a pleiotropic capacity for exhibiting regulatory T-cell responses, including the abilities to inhibit naive CD4+ T-cell activation and proliferation, decrease the production of inflammatory cytokines by activated CD4+ T cells and induce apoptosis in activated CD4+T cells. MSCs enhance the regulatory function of CD8+CD28- Tregs by increasing their expression of IL-10 and FasL. Moreover, MSCs promote the survival of CD8+CD28- Tregs, thereby increasing their proportion among the T-cell population, different from the MSC-mediated increase in CD4+CD25+ Tregs, which requires the generation and expansion of these Tregs. However, MSCs might indirectly promote the generation of CD8+CD28- Tregs, such as by inducing tolerized APCs. APCs, antigen-presenting cells; MSCs, mesenchymal stem cells; Tregs, regulatory T cells.