CD8+CD122+ T-cells have been traditionally described as antigen-specific memory T-cells that respond to previously encountered antigens more quickly and vigorously than their naïve counterparts. However, mounting evidence has demonstrated that murine CD8+CD122+ T-cells exhibit a central memory phenotype (CD44highCD62Lhigh), regulate T cell homeostasis, and act as regulatory T-cells (Treg) by suppressing both autoimmune and alloimmune responses. Importantly, naturally occurring murine CD8+CD122+ Tregs are more potent in immunosuppression than their CD4+CD25+ counterparts. They appear to be acting in an antigen-non-specific manner. Human CD8+CXCR3+ T-cells are the equivalent of murine CD8+CD122+ Tregs and also exhibit central memory phenotypes. In this mini-review article, we will summarize recent progresses in their phenotypes, homeostatic expansion, antigen-specificity, roles in the suppression of alloimmune and autoimmune responses, and the mechanisms underlying their inhibitory function.
Cigarette smoking (CS) regulates both innate and adaptive immunity and causes numerous diseases, including cardiovascular, respiratory, and autoimmune diseases, allergies, cancers, and transplant rejection. Therefore, smoking poses a serious challenge to the healthcare system worldwide. Epidemiological studies have always shown that CS is one of the major risk factors for transplant rejection, even though smoking plays redundant roles in regulating immune responses. The complex roles for smoking in immunoregulation are likely due to molecular and functional diversities of cigarette smoke components, including carbon monoxide (CO) and nicotine. Especially, CO has been shown to induce immune tolerance. Although CS has been shown to impact transplantation by causing complications and subsequent rejection, it is overlooked whether CS interferes with transplant tolerance. We have previously demonstrated that cigarette smoke exposure reverses long-term allograft survival induced by costimulatory blockade. Given that CS impacts both adaptive and innate immunity and that it hinders long-term transplant survival, our perspective is that CS impacts transplant tolerance. Here, we review impacts of CS on major immune cells that are critical for transplant outcomes and propose the cellular and molecular mechanisms underlying its effects on alloimmunity and transplant survival. Further investigations are warranted to fully understand why CS exerts deleterious rather than beneficial effects on transplant survival even if some of its components are immunosuppressive.
Due to vigorous alloimmunity, an allograft is usually rejected without any conventional immunosuppressive treatment. However, continuous global immunosuppression may cause severe side effects, including tumors and infections. Mounting evidence has shown that cyclosporine (CsA), a common immunosuppressant used in clinic, impedes allograft tolerance by dampening regulatory T cells (Tregs), although it inhibits allograft rejection at the same time. Therefore, it is necessary to seek an alternative immunosuppressive drug that spares Tregs with high efficiency in suppression but low toxicity. In this study, we investigated the capacity of emodin, an anthraquinone molecule originally extracted from certain natural plants, to prolong transplant survival in a mouse model and explored the cellular and molecular mechanisms underlying its action. We found that emodin significantly extended skin allograft survival and hindered CD3+ T cell infiltration in the allograft, accompanied by an increase in CD4+Foxp3+ and CD8+CD122+ Treg frequencies and numbers but a reduction in effector CD8+CD44highCD62Llow T cells in recipient mice. Emodin also inhibited effector CD8+ T cells proliferation in vivo. However, CD4+CD25+, but not CD8+CD122+, Tregs derived from emodin-treated recipients were more potent in suppression of allograft rejection than those isolated from control recipients, suggesting that emodin also enhances the suppressive function of CD4+CD25+ Tregs. Interestingly, depleting CD25+ Tregs largely reversed skin allograft survival prolonged by emodin while depleting CD122+ Tregs only partially abrogated the same allograft survival. Furthermore, we found that emodin hindered dendritic cell (DC) maturation and reduced alloantibody production posttransplantation. Finally, we demonstrated that emodin inhibited in vitro proliferation of T cells and blocked their mTOR signaling as well. Therefore, emodin may be a novel mTOR inhibitor that suppresses alloimmunity by inducing both CD4+FoxP3+ and CD8+CD122+ Tregs, suppressing alloantibody production, and hindering DC maturation. Thus, emodin is a newly emerging immunosuppressant and could be utilized in clinical transplantation in the future.
Previous studies have demonstrated that patients develop de novo cardiovascular risk factors after hematopoietic stem cell transplantation (HSCT) (1). The risk of developing metabolic syndrome in HSCT survivors was increased compared with normal subjects (2,3). HSCT survivors were also more likely to develop hyperinsulinemia, impaired glucose tolerance, hypertriglyceridemia, and abdominal obesity than were non-HSCT patients or healthy controls (4). However, it remains unclear whether increased cardiovascular risk factors are directly associated with transplantation-related factors, including total body irradiation, immunosuppression, and graft-versus-host disease. While HSCT-related treatments in recipients have been proposed as causes of increased cardiovascular risk factors in HSCT survivors (1), other studies have shown that there is no clear correlation between HSCT-related treatments and cardiovascular risk factors (2,3).Bejar et al previously examined whether the presence of cardiovascular risk factors in bone marrow donors contributed to increased cardiovascular risks in recipients. They found that bone marrow cells derived from rats with hypercholesterolemia, obesity, and insulin resistance transferred an increased thrombotic risk to healthy recipients (5). The platelets derived from the bone marrow of diabetic fatty rats exhibited a dysregulated endoplasmic reticulum stress protein that promoted thrombosis in recipients (6). Using diabetic fatty rat models in the current study, the authors discovered that bone marrow cells from diabetic rat donors with cardiovascular risk factors induced proatherogenic alterations in the cholesterol profiles of otherwise healthy recipients by increasing low-density lipoprotein (LDL), but not triglyceride, levels, whereas bone marrow cells derived from healthy donors did not (7). These findings suggest that a cardiovascular risk factor can be transferred from donors to recipients of bone marrow transplants and that the risk factor does not result from bone marrow transplantation itself or transplantation-related treatments. These novel findings may be implicated in clinical HSCT for screening healthy donors.Mechanisms underlying the transfer of cardiovascular risk factors from bone marrow donors to recipients remain unclear. Current studies by Bejar et al revealed that proinflammatory cytokines interleukin (IL)-1b and tumor necrosis factor (TNF)a in the liver were increased in recipients of bone marrow cells derived from diabetic rat donors compared with those from healthy control donors. They also demonstrated direct correlations between liver macrophage markers (CD68 and CD163) and the expression of genes (Lpl, Fabp4, and CD36) that are associated with liver lipid homeostasis (7). Kupffer cells are liver-resident macrophages that can produce proinflammatory cytokines, including IL-1b and TNFa, which, in turn, interfere with lipid metabolism (8). Therefore, the authors proposed that bone marrow cells derived from donors with cardiovascular risk factors promoted the recr...
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